Skip Navigation
Skip to contents

Cancer Res Treat : Cancer Research and Treatment

Search
Advanced Search
OPEN ACCESS
mobile search button mobile menu button

Articles

Page Path
HOME > Cancer Res Treat > Volume 46(3); 2014 > Article
Review Article Regulation and Role of EZH2 in Cancer
Hirohito Yamaguchi1, Mien-Chie Hung1,2,3,4,
Cancer Research and Treatment : Official Journal of Korean Cancer Association 2014;46(3):209-222.
DOI: https://doi.org/10.4143/crt.2014.46.3.209
Published online: July 15, 2014

1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Graduate School of Biomedical Sciences, The University of Texas, Houston, TX, USA

3Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan

4Asia University, Taichung, Taiwan

Correspondence: Mien-Chie Hung   Department of Molecular and Cellular Oncology, Unit 108, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA  
Tel: 1-713-792-3668 Fax: 1-713-794-3270 E-mail: mhung@mdanderson.org
• Received: May 9, 2014   • Accepted: June 5, 2014

Copyright © 2014 by the Korean Cancer Association

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • 42,117 Views
  • 862 Download
  • 241 Web of Science
  • 215 Crossref
  • 247 Scopus
next
Full Article

Download PDF Download PDF

  • Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.
  • Key words: EZH2, PRC2, Neoplasms, Genetic transcription, Untranslated RNA, MicroRNAs, Post-translational protein processing
Polycomb group proteins are initially identified as regulators controlling the establishment of body segmentation by silencing hox genes expression in Drosophila. Later, they were foun to be epigenetic regulators that are critical for multiple cellular functions, including stem cell maintenance and differentiation [1]. Polycomb group proteins are well conserved between Drosophila and humans and are involved in gene silencing. Two major polycomb repressive complexes, Polycomb repressive complex (PRC) 1 and PRC2, control gene silencing through post-translational modifications of histone proteins [2]. PRC1 consists of Bmi1, Ring1b, CBX4, and PHC subunits and induces histone 2A lysine 119 ubiquitination (H2AK119ub1). In contrast, PRC2 consists primarily of enhancer of zeste homolog 2 (EZH2), EED, SUZ12, and RbAp48 and catalyzes the methylation of histone H3 lysine 27 (H3K27) to generate trimethyl-H3K27 (H3K27me3) [3]. PRC1 enhances the effects of PRC2 by recognizing H3K27me3 and interacting with it, but these complexes can also repress gene expression independently [2]. EZH2 is the catalytic subunit of PRC2, and growing evidence demonstrates that EZH2 is essential for cancer initiation, development, progression, metastasis, and drug resistance. Therefore, EZH2 is currently considered a promising drug target, and multiple inhibitors of EZH2 have been developed, some of which are in clinical trials. In this review, we introduce current information regarding the molecular mechanisms by which EZH2 expression/activity is regulated as well as the role of EZH2 in oncogenic signaling pathways. Moreover, we focus on the therapeutic potential of EZH2 and discuss possible approaches to targeting EZH2.
EZH2 is frequently overexpressed in many cancer types and is critical for cancer cell proliferation and survival. Indeed, the regulators of EZH2 expression are also critical for cell proliferation, tumorigenesis, and stem cell maintenance (Fig. 1). For example, Myc binds to EZH2 promoter and directly activates its transcription, and EZH2 expression is correlated with Myc expression in prostate cancer [4]. Myc also upregulates EZH2 expression by downregulating miRNA 101 (miR-101), miR-26a, and miR-26b [4-7]. In contrast, c-Myc expression is also positively regulated by EZH2 in glioblastoma, although the underlying mechanism is uncertain [8]. In addition to Myc, another cell cycle regulator, E2F, positively controls EZH2 transcription, and EZH2 is critical for the regulation of pRB-E2F pathway [9]. ANCCA, a co-activator of androgen receptor (AR) and binding protein of E2F, can enhance E2F-mediated EZH2 transcription in prostate cancer cells [10,11]. In Ewing tumors, EWS-FLI1 fusion oncoprotein directly regulates EZH2 gene expression [12]. SOX4, one of the key regulators of stem cells, directly regulates the expression of EZH2 mRNA, which is critical for SOX4-mediated epithelial-mesenchymal transition (EMT) [13]. Moreover, NF-Y, STAT3, and ETS transcription factors directly regulate EZH2 transcription in epithelial ovarian, colorectal, and prostate cancer cells, respectively [14-16]. Both Elk-1 and HIF1 directly regulates EZH2 transcription that is associated with aggressive breast cancer [17,18].
In addition to transcriptional regulators, multiple miRNAs have been shown to directly regulate EZH2 expression, and many of them are deregulated in cancer. So far, miR-25, -26a, -30d, -98, -101, -124, -137, -138, -144, -214, -let-7, and -let-7a have been shown to be able to downregulate EZH2 expression directly in cancer cells. The downregulation of these miRNAs and the resulting upregulation of EZH2 seem to be critical for the aggressive behaviors of various cancers. These miRNAs include miR-25 and -30d in thyroid cancer [19]; miR-26a in lymphoma, nasopharyngeal carcinoma (NPC), and breast and prostate cancer [6,7,20,21]; mR-101 in NPC, glioblastoma multiforme (GBM), and prostate, bladder, gastric, head and neck (HN), and non-small cell lung cancer (NSCLC) [22-27]; miR-138 in HN cancer, GBM, and NSCLC [28-30]; let-7s in prostate cancer and NPC [31,32]; miR-124 in hepatocellular carcinoma (HCC) and gastric cancer [33,34]; miR-98 in NPC and gastric cancer [35,36]; miR-137 in melanoma [37]; miR-144 in bladder cancer [38]; and miR214 in gastric cancer and HCC [35,39]. These miRNAs are tumor suppressor like miRNA and, interestingly, miR-26a has been also shown to be regulated by epidermal growth factor receptor-mediated Ago2 phosphorylation under hypoxia condition [40].
EZH2, EED, SUZ12, and RbAp48 are core proteins in PRC2, but their DNA binding activity is weak. Thus, PRC2 requires other factors to recruit it to specific loci. Multiple transcription factors also interact with PRC2 to recruit it to specific loci, and some of them have been shown to play a critical role in cancer. Transcription factor Yin Yang 1 (YY1) interacts with EZH2 and recruits it to the specific sites to regulate gene silencing. YY1 and PRC2 are involved in muscle differentiation [41]. In endometrioid endometrial carcinoma, EZH2 and YY1 repress tumor suppressor APC and promote cell growth [42]. Snail forms a complex with EZH2 via histone deacetylase (HDAC)1/2 and recruits it to E-cadherin promoter to suppress E-cadherin expression in NPC [43]. c-Myc interacts with EZH2 and suppresses miR-101 expression in HCC, whereas MYCN interacts with EZH2 and inhibits tumor suppressor clusterin in neuroblastoma [5,44]. In addition to oncogenic transcription factor, PRC2 interacts with tumor suppressor proteins and contributes to tumor suppressor function. For example, tumor suppressor scaffold attachment factor B1 (SAFB1) interacts with PRC2 and AR and represses AR transcription machinery via H3K27me3 in prostate cancer cells [45]. Hypermethylated in cancer 1 (HIC1), which is a tumor suppressor gene that is frequently silenced or deleted in various cancers, recruits PRC2 to its target genes [46]. PER2 can interact with PRC2 and Oct1, and recruit them to Snail Slug and Twist promoters and inhibit their gene expression, thereby using PRC2 as a tumor suppressor [47]. Other transcription factors such as E2F6, Twist-1, RUNX3, and CCCTC binding factor interact with PRC2 and recruit it to repress specific target genes, but their roles in cancer are uncertain [48-51].
In addition to proteins, noncoding RNAs (ncRNAs) interact with EZH2 and play an important role in the recruitment of EZH2 to several specific loci. In cancer, HOTAIR is one of the most well described large intervening ncRNAs that interacts with EZH2 [52]. Overexpression of HOTAIR in breast cancer cells enhances cancer cell invasion and metastasis that require PRC2, while the loss of HOTAIR reduces them. HOTAIR plays an oncogenic role in colorectal cancer, pancreatic cancer, and NSCLC [53-55]. Remarkably, HOTAIR can interact with PRC2 and the LSD1/CoREST/REST repressor complex (which is responsible for the demethylation of H3K4me2), serving as a scaffold to recruit two distinct histone modifiers to the same loci [56].
In addition to HOTAIR, several ncRNAs have been shown to interact with EZH2 and are involved in EZH2-mediated cancer aggressiveness. These include HEIH in HCC [57], PCAT-1 in prostate cancer [58], and H19 and linc-UBC1 in bladder cancer [59,60]. Several other ncRNAs such as Xist, Six3OS, Meg3, AS1DHRS4, and ANCR have been shown to interact with PRC2 and regulate X-chromosome inactivation, cell differentiation, and stem cell maintenance [61-65], but their roles in cancer have not been identified. In addition to ncRNA, miR-320 directly interacts with EZH2 and argonaute-1 (AGO1) and recruits them to the promoter region of the cell cycle gene POLR3D and silences it [66]. Moreover, EZH2 also interacts with multiple intronic RNAs. Among them, the intronic RNA for SMYD3 (H3K4 methyltransferase) reduces SMYD3 expression, cell proliferation, and xenograft tumor growth in human colorectal cancer cells [67]. Interestingly, BRCA1 negatively regulates PRC2 activity by inhibiting the association between EZH2 and HOTAIR, and the loss of BRCA1 contributes to an aggressive breast cancer phenotype [68]. EZH2-HOTAIR or EZH2-Xist interaction is also regulated by CDK-mediated phosphorylation, as described in the next section [69]. PRC2 co-factor JARID2 also mediates the interaction of PRC2 and ncRNAs such as Xist and Meg3 [65,70].
Growing evidence shows that EZH2 activity and stability are regulated by post-translational modifications and that these modifications are critical for the biological function of PRC2 (Fig. 2). It has been reported that Akt phosphorylates EZH2 at serine 21 (S21) and inhibits its enzyme activity for H3K27me3 [71]. Later, this phosphorylation site was shown to be critical for the H3K27me3-independent function of EZH2 [72,73]. JAK2 phosphorylates EZH2 at tyrosine 641 (Y641), which promotes the interaction of EZH2 with β-TrCP and degradation of EZH2 [74]. Y641 is frequently mutated in B-cell lymphoma, and the stability and activity of the EZH2 Y641 mutant is higher than that of wild-type EZH2. Several studies have demonstrated that CDK1/2 phosphorylates EZH2 at multiple sites, including threonine 345, T416, and T487 [69,75-78]. The role of CDK-mediated phosphorylation in EZH2 function is diverse and may depend on cell types and conditions. T345 phosphorylation promotes the association between EZH2 and HOTAIR, whereas T416 phosphorylation induces the binding of NIPP1 to EZH2, and both T345 and T416 phosphorylation are critical for the recruitment of EZH2 to specific loci [69,78]. Moreover, NIPP1 maintains EZH2 phosphorylation by inhibiting its dephosphorylation by PP1 [78]. It has been showed that CDK1 phosphorylates EZH2 at T487 and that the phosphorylation induces the dissociation of EZH2 from PRC2, resulting in the inactivation of EZH2 and a reduction in cancer cell invasion [77]. In contrast, EZH2 phosphorylation at T345 promotes cell migration and proliferation [75]. T345 and T487 phosphorylation in EZH2 also promotes EZH2 ubiquitination and degradation [76].
In neurons, ATM interacts with and phosphorylates EZH2 at S734, and S734 phosphorylation of EZH2 reduces PRC2 assembly, EZH2 stability, and cell death in neurons [79]. ATM-mediated phosphorylation of EZH2 is critical for neurodegeneration in ataxia-telangiectasia, which is caused by ATMmutation [79]. Moreover, p38 phosphorylates EZH2 at threonine 372 (T372) and promotes its interaction with YY1, which is critical for tumor necrosis factor-mediated Pax7 inhibition and muscle stem cell proliferation [80]. The role of ATM- or p38-mediated phosphorylation in cancer is not yet certain.
Recently, EZH2 was shown to interact with O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) and to be O-GlcNAcylated at S75 in vivo. Interestingly, OGT upregulates cellular H3K27me3 levels, and S75 to alanine (S75A) mutant EZH2 is less stable than wild-type EZH2, suggesting that the O-GlcNAcylation of EZH2 may play a role in EZH2 stability and H3K27me3 [81]. EZH2 is also sumoylated in vivo and in vivo, but the functional significance of its sumoylation has not been determined [82]. EZH2 ubiquitination is critical for its protein stability. It has been shown that Smurf2 functions as an E3 ligase for EZH2 in human mesenchymal stem cells and promotes neuron differentiation [83]. β-TrCP and PRAJA1 also function as E3 ligases for EZH2 [74,84].
EZH2 is required for cancer cell proliferation, migration, invasion, and EMT, all of which are associated with cancer initiation, progression, and metastasis. More importantly, EZH2 is closely associated with stem cell properties, especially cancer stem cell properties, and tumor-initiating cell function [8,17,85].
In diffuse large B-cell lymphoma and follicular lymphoma, recurrent somatic mutations in the EZH2 gene have been identified, which changes amino acid tyrosine 641 (Y641) in EZH2, thereby altering its enzyme activity [86]. These mutations were originally considered a loss-of-function mutation because it reduces EZH2 methyltransferase activity toward an unmodified substrate. However, mono- to di- and di- to trimethylation activity is higher in Y641 mutant EZH2 than in wild-type EZH2. Y641 mutant EZH2 actually has higher activity of mono- to di- and di- to tri-methylation than wildtype EZH2 [87]. In addition, the Y641 mutation is always a heterogeneous mutation, and diffuse large B-cell lymphoma and follicular lymphoma with EZH2 mutation express both wild-type and Y641 mutant EZH2, resulting in higher H3K27me3 in mutant cancer cells than wild-type cells [87]. Thus, the EZH2 Y641 mutation is unique gain-of-function mutation. The oncogenic role of the Y641 mutation was further confirmed in an engineered mouse model in which conditional expression of mutant EZH2 in germinal center B-cells induced germinal center hyperplasia and promoted lymphoma formation in the presence of Bcl-2 overepxression [88]. In addition to Y641 mutation, A687V and A677G mutations have been identified as activating mutations of EZH2 in B-cell lymphoma [89,90]
Recently, a K27M mutation in one of the histone H3 variants, H3.3, was found in 50% of pediatric high-grade glioma [91,92]. The cells with H3.3K27M show reduced levels of global H3K27me3 because H3.3K27M binds to and inhibits EZH2. Interestingly, H3K27me3 and EZH2 were also shown to be locally increased in hundreds of genes in cells with the H3.3K27M mutation [93]. Therefore, alterations in H3K27me3 are closely associated with glioma.
Overexpression of EZH2 is frequently observed in multiple cancer types, including prostate, breast, bladder, ovarian, lung, liver, brain, kidney, gastric, esophageal, and pancreatic cancer and melanoma [94-104]. In many of these, EZH2 expression is also correlated with higher proliferation and aggressive behavior of cancer cells as well as poor prognosis. Indeed, multiple studies have shown that overexpression of EZH2 promotes cell proliferation, migration, and/or invasion in vivo [26,43,100,105]. Furthermore, overexpression of wild-type EZH2 in mammary epithelial cells in vivo results in epithelial hyperplasia and promotes mammary tumor initiation induced by human epidermal growth factor receptor 2/neu expression [106,107].
In some types of cancer, EZH2 functions as a tumor suppressor. Inactivating mutations of EZH2 are found in patients with myeloid malignancies including myelodysplastic syndrome and myeloproliferative neoplasms, and such EZH2 mutations are associated with poor patient survival [108,109]. Mice with conditional deletions of EZH2 and TET2 in hematopoietic stem cells, the mutations of which frequently co-exist in myeloid malignancies, develop myelodysplastic syndrome and myeloproliferative neoplasms [110]. In addition to myeloid malignacies, 25% of T-cell leukemia cases have been shown to have loss-of-function mutations and deletions of the EZH2 and SUZ12 genes [111]. Indeed, conditional deletion of EZH2 in bone marrow cells causes T-cell leukemia, indicating that EZH2 functions as a tumor suppressor in T-cell leukemia as well [112]. Moreover, mice with conditional deletion of EZH2 in the pancreatic epithelium also exhibit impaired pancreatic regeneration and acceleration of K-Ras-induced neoplasia [113]. Together, these results suggest that the role of EZH2 is cell context dependent, although EZH2 functions as an oncogenic factor in the majority of solid tumors.
So far, many EZH2 target genes have been identified, and HOX genes are well-known targets for EZH2 during embryonic development. Because EZH2 frequently functions as an oncogenic factor in many cancer types, most EZH2 targets identified in cancer are tumor suppressor genes. The INK4B-ARF-INK4A tumor suppressor locus is regulated by EZH2, PRC1, and PRC2, and the suppression of these genes is also critical for development of embryo as well as cancer [114-117]. Another critical target of EZH2 in multiple cancers is the E-cadherin gene (CHD1), the downregulation of which is critical for EMT and metastasis [118-121]. EZH2 also interacts with Snail to repress E-cadherin expression [43].
In addition to these proteins, multiple EZH2 target genes have been shown to be involved in EZH2-mediated cancer aggressiveness. These target genes include stathmin and Wnt antagonists in HCC [122,123]; bone morphogenetic protein receptor 1B in GBM [85]; p57 in breast and ovarian cancers [124,125]; DAB2IP, SLIT2, TIMP2/3, and CCN3/NOV in prostate cancer [126-129]; FOXC1, HOXC10, and RAD51 in breast cancer [130-132]; CXXC4 in gastric cancer [133]; MyoD in rhabdomyosarcoma [134]; rap1GAP in HN cancer [25]; CASZ1 in neuroblastoma [135]; and RUNX3 and KLF2 in multiple cancer types [136,137]. In addition, several molecules such as Bim, TRAIL, and FBXO32 play a role in apoptosis induced by the inhibition of EZH2 [138-140]. Vasohibin1 is regulated by EZH2 in tumor-associated endothelial cells, and this regulation plays a role in tumor angiogenesis [141]. EZH2 also regulates the expression other epigenetic regulators by silencing multiple miRNAs, which are critical for the oncogenic function of EZH2 [142,143].
Although the primary function of EZH2 is gene silencing through the methylation of H3K27, accumulating evidence shows that EZH2 functions independently of H3K27me3 in various cancers (Fig. 3). Several reports have shown that EZH2 functions as a transcription activator. For example, EZH2 interacts with estrogen receptor (ER) α and β-catenin, and the complex regulates c-Myc and cyclin D1 expression in breast cancer cells [144]. Moreover, in a transgenic mouse model, EZH2 was shown to interact with β-catenin and promote its nuclear accumulation and activation in mammary epithelial cells [107]. In colon cancer cells, the DNA repair protein proliferating cell nuclear antigen (PCNA)-associated factor interacts with EZH2 and β-catenin and increases β-catenin target gene expression [145]. The effect of EZH2 on PCNA-associated factor-mediated activation of β-catenin does not require EZH2 methyltransferase activity. EZH2 also functions as a transcriptional co-activator with AR in castration-resistant prostate cancer cells [72]. Interestingly, this functional switch from a transcription silencer to an activator requires S21 phosphorylation of EZH2 by Akt, and activation of AR depends on EZH2 methyltransferase activity. In ER-negative basal-like breast cancer cells, EZH2 interacts with RelA/RelB and functions as a transcription co-activator of nuclear factor-kappa B. In contrast, EZH2 interacts with ER and represses nuclear factor-kappa B target gene expression by inducing H3K27me3 on their promoters in ER-positive luminal-like breast cancer cells [146]. In natural killer/T-cell lymphoma, EZH2, which is upregulated via Myc-mediated miRNA inhibition, directly activates cyclin D transcription and promotes cell proliferation independent of methyltransferase activity [147].
EZH2 also methylates proteins other than histone H3 and modulates their functions (Fig. 3). For example, EZH2 interacts with and methylates STAT3, resulting in increased tyrosine phosphorylation and activation of STAT3 [73]. Strikingly, AKT-mediated phosphorylation at S21 in EZH2 is critical for the interaction of EZH2 with STAT3, and this AKT-EZH2-STAT3 pathway is critical for the maintenance of glioblastoma stem cells and tumor progression. EZH2 also mono-methylates tumor suppressor, retinoic acid-related orphan nuclear receptor α (RORα) [148]. Mono-methylated RORα is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex and undergoes ubiquitination and degradation. EZH2 also methylates GATA4 and inhibits its activity by inhibiting its interaction with p300 [149], although the role of this methylation in cancer has not been established.
EZH2 also regulates cellular functions other than transcription. Cytosolic EZH2, the level of which is higher in prostate cancer cells than in normal prostate cells, regulates actin polymerization [150,151]. However, the underlying molecular mechanism has not yet been identified. In addition, PRC2 is recruited to sites of DNA damage in a poly(ADP-ribose) polymerase-dependent manner and is involved in DNA damage repair [152]. EZH2 knockdown reduces DNA double-strand break repair and sensitizes cells to ionizing radiation. Interestingly, EZH2 and BRCA1 regulate each other and are involved in several cellular functions. Knockdown of EZH2 upregulates BRCA1 protein, which is important for the downregulation of proliferation induced by the inhibition of EZH2 in ER-negative breast cancer [153]. Consistently, EZH2 induces BRCA1 nuclear exclusion and inhibits its activity, which contributes to chromosome instability in breast cancer [154]. In contrast, BRCA1 also regulates EZH2 activity. BRCA1 inhibits EZH2-HOTAIR interaction as previously described herein [68]. Moreover BRCA1-deficient cells have higher EZH2 expression and are thereby more sensitive to EZH2 inhibition than BRCA1-proficient cells [155]. Thus, EZH2-BRCA1 interaction is complicated, and further studies may be necessary.
Because EZH2 is a central regulator of proliferation, migration, invasion and stem cell properties of cancer cells, it is considered a potential drug target. 3-Deazaneplanocin A (DZNep), which is an inhibitor of S-adenosylhomocysteine hydrolase, downregulates PRC2 proteins including EZH2 and inhibits PRC2 activity [139]. DZNep treatment indeed induces the downregulation of H3K27me3, reactivates PRC2 target genes, and effectively induces apoptosis in cancer cells but not in normal cells [139]. This compound has been widely used in preclinical and in vitro studies to investigate the function of EZH2 in cancer and has been shown to effectively inhibit cell proliferation and tumor growth in various cancers [156-159]. Remarkably, the killing effect of DZNep is about 20-fold greater in BRCA1-deficient cells than in BRCA1-proficient mammary tumor cells although the underlying mechanism is not known [155]. DZNep was recently shown to induce erythroid differentiation independent of EZH2, suggesting that the effects of DZNep may be partially independent of EZH2 inhibition [160]. However, because DZNep downregulates EZH2 protein levels, it is expected to inhibit the methylation-independent functions of EZH2 [147].
Recently, several highly selective small molecule inhibitors against EZH2, such as GSK126, EPZ005687, EI1, and EPZ-6438, have been developed [161-164]. These inhibitors exhibit higher effects against the lymphoma with Y641 activation mutation of EZH2 than the one with wild-type EZH2. Currently, EPZ-6438 is being tested in clinical trials of patients with B-cell lymphoma and advanced solid tumors.
In addition to specific EZH2 inhibitors, several other drugs and compounds have been reported to be able to downregulate EZH2, and the downregulation of EZH2 is critical for their anti-cancer activity. These include curcumin [165,166], omega-3 polyunsaturated fatty acids [167], and sorafenib [168]. Moreover, inhibition of EZH2 also sensitizes cancer cells to various other anti-cancer drugs, such as HDAC inhibitors, imatinib, gemcitabine, paclitaxel, and cisplatin [27,98,140,169-174].
EZH2 is a critical regulator of cell proliferation, migration/invasion, and stemness in cancer and functions as an oncogenic factor in most solid tumors. Indeed, EZH2 inhibitors have shown promising anti-cancer activity against EZH2-active or -overexpressing cancer cells in multiple preclinical studies, and EPZ-6438 is currently under clinical trials. Inhibition of EZH2 also enhances several existing anticancer drugs, suggesting the potential for combination therapy using EZH2 inhibitors. Moreover, EZH2 is frequently overexpressed in multiple cancer types and is associated with poor prognosis. Therefore, EZH2 may serve as a valuable prognostic marker. In the future, additional studies will be required to establish effective combination treatment strategies and identify appropriate biomarkers in various cancer types to predict sensitivity to EZH2 inhibitors.
Herein, we introduced multiple mechanisms of EZH2 regulation, including transcriptional regulation, mRNA regulation by miRNAs, accessibility to DNA via DNA binding proteins and ncRNAs, and post-translational modifications. Because these upstream regulators of EZH2 most likely control multiple targets other than EZH2, the inhibition of these mechanisms may be an alternative approach to targeting EZH2 and even more effective than EZH2 inhibitors alone. For instance, the kinases that phosphorylate EZH2 also phosphorylate many substrates and activate other signaling pathways. Indeed, CDK inhibitors have shown anti-tumor activity in preclinical studies and are currently being tested in clinical trials. The effects of CDK inhibitors may be achieved partially through the attenuation of EZH2 activity, and EZH2 may serve as a biomarker for these drugs. Thus, the identification of upstream regulators of EZH2 may lead to effective therapeutic strategies for various cancers.

Conflict of interest relevant to this article was not reported.

Acknowledgements
This work was supported by the following grants: National Institutes of Health (CA109311, CA099031); Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW103-TD-B-111; Taiwan), the Program for Stem Cell and Regenerative Medicine Frontier Research (NSC102-2321-B-039; Taiwan).
Fig. 1.
Regulators of EZH2 expression and DNA targeting in cancer. EZH2 expression is regulated by various oncogenic transcription factors and tumor suppressor miRNAs. Access to the specific DNA sites is regulated by various transcription factors and noncoding RNAs (ncRNAs).
crt-46-3-209f1.gif
Fig. 2.
Post-translational modifications of EZH2. EZH2 is phosphorylated at S21, T345, T372, T416, T487, Y641, and S734 by the indicated kinases. S75 is glycosylated by O-linked N-acetylglucosamine transferase (OGT). In addition, EZH2 is ubiquitinated by Smurf2, β-TrCP, and PRAJA1 and undergoes degradation.
crt-46-3-209f2.gif
Fig. 3.
Various functions of EZH2 in human cancer. EZH2 silences multiple tumor suppressors such as INK4A/ARF and E-cadherin via canonical H3K27me3. EZH2 also methylates substrates other than H3K27, such as STAT3 and RORα. Furthermore, EZH2 has a methylase-independent function.
crt-46-3-209f3.gif
  • 1. Morey L, Helin K. Polycomb group protein-mediated repression of transcription. Trends Biochem Sci. 2010;35:323–32. ArticlePubMed
  • 2. Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol. 2009;10:697–708. ArticlePubMed
  • 3. O'Meara MM, Simon JA. Inner workings and regulatory inputs that control Polycomb repressive complex 2. Chromosoma. 2012;121:221–34. ArticlePubMedPMC
  • 4. Koh CM, Iwata T, Zheng Q, Bethel C, Yegnasubramanian S, De Marzo AM. Myc enforces overexpression of EZH2 in early prostatic neoplasia via transcriptional and post-transcriptional mechanisms. Oncotarget. 2011;2:669–83. ArticlePubMedPMC
  • 5. Wang L, Zhang X, Jia LT, Hu SJ, Zhao J, Yang JD, et al. c-Mycmediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma. Hepatology. 2014;59:1850–63. ArticlePubMed
  • 6. Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF, et al. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood. 2008;112:4202–12. ArticlePubMed
  • 7. Salvatori B, Iosue I, Djodji Damas N, Mangiavacchi A, Chiaretti S, Messina M, et al. Critical role of c-Myc in acute myeloid leukemia involving direct regulation of miR-26a and histone methyltransferase EZH2. Genes Cancer. 2011;2:585–92. ArticlePubMedPMC
  • 8. Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, et al. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 2009;69:9211–8. ArticlePubMed
  • 9. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003;22:5323–35. ArticlePubMedPMC
  • 10. Kalashnikova EV, Revenko AS, Gemo AT, Andrews NP, Tepper CG, Zou JX, et al. ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2. Cancer Res. 2010;70:9402–12. ArticlePubMedPMC
  • 11. Duan Z, Zou JX, Yang P, Wang Y, Borowsky AD, Gao AC, et al. Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate via MLL histone methylase complex. Prostate. 2013;73:455–66. ArticlePubMed
  • 12. Richter GH, Plehm S, Fasan A, Rossler S, Unland R, Bennani-Baiti IM, et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc Natl Acad Sci U S A. 2009;106:5324–9. ArticlePubMedPMC
  • 13. Tiwari N, Tiwari VK, Waldmeier L, Balwierz PJ, Arnold P, Pachkov M, et al. Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell. 2013;23:768–83. ArticlePubMed
  • 14. Garipov A, Li H, Bitler BG, Thapa RJ, Balachandran S, Zhang R. NF-YA underlies EZH2 upregulation and is essential for proliferation of human epithelial ovarian cancer cells. Mol Cancer Res. 2013;11:360–9. ArticlePubMedPMC
  • 15. Lin YW, Ren LL, Xiong H, Du W, Yu YN, Sun TT, et al. Role of STAT3 and vitamin D receptor in EZH2-mediated invasion of human colorectal cancer. J Pathol. 2013;230:277–90. ArticlePubMed
  • 16. Kunderfranco P, Mello-Grand M, Cangemi R, Pellini S, Mensah A, Albertini V, et al. ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer. PLoS One. 2010;5:e10547ArticlePubMedPMC
  • 17. Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell. 2011;19:86–100. ArticlePubMedPMC
  • 18. Fujii S, Tokita K, Wada N, Ito K, Yamauchi C, Ito Y, et al. MEKERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene. 2011;30:4118–28. ArticlePubMed
  • 19. Esposito F, Tornincasa M, Pallante P, Federico A, Borbone E, Pierantoni GM, et al. Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2. J Clin Endocrinol Metab. 2012;97:E710–8. ArticlePubMed
  • 20. Zhang B, Liu XX, He JR, Zhou CX, Guo M, He M, et al. Pathologically decreased miR-26a antagonizes apoptosis and facilitates carcinogenesis by targeting MTDH and EZH2 in breast cancer. Carcinogenesis. 2011;32:2–9. ArticlePubMed
  • 21. Lu J, He ML, Wang L, Chen Y, Liu X, Dong Q, et al. MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. Cancer Res. 2011;71:225–33. ArticlePubMed
  • 22. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008;322:1695–9. ArticlePubMedPMC
  • 23. Friedman JM, Liang G, Liu CC, Wolff EM, Tsai YC, Ye W, et al. The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res. 2009;69:2623–9. ArticlePubMed
  • 24. Wang HJ, Ruan HJ, He XJ, Ma YY, Jiang XT, Xia YJ, et al. MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer. 2010;46:2295–303. ArticlePubMed
  • 25. Banerjee R, Mani RS, Russo N, Scanlon CS, Tsodikov A, Jing X, et al. The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma. Oncogene. 2011;30:4339–49. ArticlePubMedPMC
  • 26. Smits M, Nilsson J, Mir SE, van der Stoop PM, Hulleman E, Niers JM, et al. miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget. 2010;1:710–20. ArticlePubMedPMC
  • 27. Zhang JG, Guo JF, Liu DL, Liu Q, Wang JJ. MicroRNA-101 exerts tumor-suppressive functions in non-small cell lung cancer through directly targeting enhancer of zeste homolog 2. J Thorac Oncol. 2011;6:671–8. ArticlePubMed
  • 28. Liu X, Wang C, Chen Z, Jin Y, Wang Y, Kolokythas A, et al. MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines. Biochem J. 2011;440:23–31. ArticlePubMedPMC
  • 29. Qiu S, Huang D, Yin D, Li F, Li X, Kung HF, et al. Suppression of tumorigenicity by microRNA-138 through inhibition of EZH2-CDK4/6-pRb-E2F1 signal loop in glioblastoma multiforme. Biochim Biophys Acta. 2013;1832:1697–707. ArticlePubMed
  • 30. Zhang H, Zhang H, Zhao M, Lv Z, Zhang X, Qin X, et al. MiR-138 inhibits tumor growth through repression of EZH2 in nonsmall cell lung cancer. Cell Physiol Biochem. 2013;31:56–65. ArticlePubMed
  • 31. Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, et al. Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS One. 2012;7:e33729ArticlePubMedPMC
  • 32. Cai K, Wan Y, Sun G, Shi L, Bao X, Wang Z. Let-7a inhibits proliferation and induces apoptosis by targeting EZH2 in nasopharyngeal carcinoma cells. Oncol Rep. 2012;28:2101–6. ArticlePubMed
  • 33. Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP, et al. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 2012;61:278–89. ArticlePubMed
  • 34. Xie L, Zhang Z, Tan Z, He R, Zeng X, Xie Y, et al. microRNA- 124 inhibits proliferation and induces apoptosis by directly repressing EZH2 in gastric cancer. Mol Cell Biochem. 2014;Mar. 22[Epub]. http://dx.doi.org/10.1007/s11010-014-2028-0Article
  • 35. Huang SD, Yuan Y, Zhuang CW, Li BL, Gong DJ, Wang SG, et al. MicroRNA-98 and microRNA-214 post-transcriptionally regulate enhancer of zeste homolog 2 and inhibit migration and invasion in human esophageal squamous cell carcinoma. Mol Cancer. 2012;11:51.ArticlePubMedPMC
  • 36. Alajez NM, Shi W, Hui AB, Bruce J, Lenarduzzi M, Ito E, et al. Enhancer of Zeste homolog 2 (EZH2) is overexpressed in recurrent nasopharyngeal carcinoma and is regulated by miR-26a, miR-101, and miR-98. Cell Death Dis. 2010;1:e85ArticlePubMedPMC
  • 37. Luo C, Tetteh PW, Merz PR, Dickes E, Abukiwan A, Hotz-Wagenblatt A, et al. miR-137 inhibits the invasion of melanoma cells through downregulation of multiple oncogenic target genes. J Invest Dermatol. 2013;133:768–75. ArticlePubMed
  • 38. Guo Y, Ying L, Tian Y, Yang P, Zhu Y, Wang Z, et al. miR-144 downregulation increases bladder cancer cell proliferation by targeting EZH2 and regulating Wnt signaling. FEBS J. 2013;280:4531–8. ArticlePubMed
  • 39. Xia H, Ooi LL, Hui KM. MiR-214 targets beta-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS One. 2012;7:e44206ArticlePubMedPMC
  • 40. Shen J, Xia W, Khotskaya YB, Huo L, Nakanishi K, Lim SO, et al. EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2. Nature. 2013;497:383–7. ArticlePubMedPMC
  • 41. Caretti G, Di Padova M, Micales B, Lyons GE, Sartorelli V. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 2004;18:2627–38. ArticlePubMedPMC
  • 42. Yang Y, Zhou L, Lu L, Wang L, Li X, Jiang P, et al. A novel miR-193a-5p-YY1-APC regulatory axis in human endometrioid endometrial adenocarcinoma. Oncogene. 2013;32:3432–42. ArticlePubMed
  • 43. Tong ZT, Cai MY, Wang XG, Kong LL, Mai SJ, Liu YH, et al. EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene. 2012;31:583–94. ArticlePubMed
  • 44. Corvetta D, Chayka O, Gherardi S, D'Acunto CW, Cantilena S, Valli E, et al. Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: functional and therapeutic implications. J Biol Chem. 2013;288:8332–41. ArticlePubMedPMC
  • 45. Mukhopadhyay NK, Kim J, You S, Morello M, Hager MH, Huang WC, et al. Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2. Oncogene. 2014;33:3235–45. ArticlePubMedPMC
  • 46. Boulay G, Dubuissez M, Van Rechem C, Forget A, Helin K, Ayrault O, et al. Hypermethylated in cancer 1 (HIC1) recruits polycomb repressive complex 2 (PRC2) to a subset of its target genes through interaction with human polycomb-like (hPCL) proteins. J Biol Chem. 2012;287:10509–24. ArticlePubMedPMC
  • 47. Hwang-Verslues WW, Chang PH, Jeng YM, Kuo WH, Chiang PH, Chang YC, et al. Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy. Proc Natl Acad Sci U S A. 2013;110:12331–6. ArticlePubMedPMC
  • 48. Zhang H, Niu B, Hu JF, Ge S, Wang H, Li T, et al. Interruption of intrachromosomal looping by CCCTC binding factor decoy proteins abrogates genomic imprinting of human insulin-like growth factor II. J Cell Biol. 2011;193:475–87. ArticlePubMedPMC
  • 49. Leseva M, Santostefano KE, Rosenbluth AL, Hamazaki T, Terada N. E2f6-mediated repression of the meiotic Stag3 and Smc1beta genes during early embryonic development requires Ezh2 and not the de novo methyltransferase Dnmt3b. Epigenetics. 2013;8:873–84. ArticlePubMedPMC
  • 50. Cakouros D, Isenmann S, Cooper L, Zannettino A, Anderson P, Glackin C, et al. Twist-1 induces Ezh2 recruitment regulating histone methylation along the Ink4A/Arf locus in mesenchymal stem cells. Mol Cell Biol. 2012;32:1433–41. ArticlePubMedPMC
  • 51. Ciavatta DJ, Yang J, Preston GA, Badhwar AK, Xiao H, Hewins P, et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest. 2010;120:3209–19. ArticlePubMedPMC
  • 52. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6. ArticlePubMedPMC
  • 53. Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, et al. Long noncoding RNA HOTAIR regulates polycombdependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011;71:6320–6. ArticlePubMed
  • 54. Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, et al. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013;32:1616–25. ArticlePubMedPMC
  • 55. Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W, et al. The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS One. 2013;8:e77293ArticlePubMedPMC
  • 56. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93. ArticlePubMedPMC
  • 57. Yang F, Zhang L, Huo XS, Yuan JH, Xu D, Yuan SX, et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011;54:1679–89. ArticlePubMed
  • 58. Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol. 2011;29:742–9. ArticlePubMedPMC
  • 59. Luo M, Li Z, Wang W, Zeng Y, Liu Z, Qiu J. Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett. 2013;333:213–21. ArticlePubMed
  • 60. He W, Cai Q, Sun F, Zhong G, Wang P, Liu H, et al. linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer. Biochim Biophys Acta. 2013;1832:1528–37. ArticlePubMed
  • 61. Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science. 2008;322:750–6. ArticlePubMedPMC
  • 62. Rapicavoli NA, Poth EM, Zhu H, Blackshaw S. The long noncoding RNA Six3OS acts in trans to regulate retinal development by modulating Six3 activity. Neural Dev. 2011;6:32.ArticlePubMedPMC
  • 63. Li Q, Su Z, Xu X, Liu G, Song X, Wang R, et al. AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans. Proc Natl Acad Sci U S A. 2012;109:14110–5. ArticlePubMedPMC
  • 64. Zhu L, Xu PC. Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem Biophys Res Commun. 2013;432:612–7. ArticlePubMed
  • 65. Kaneko S, Bonasio R, Saldana-Meyer R, Yoshida T, Son J, Nishino K, et al. Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin. Mol Cell. 2014;53:290–300. ArticlePubMedPMC
  • 66. Kim DH, Saetrom P, Snove O Jr, Rossi JJ. MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc Natl Acad Sci U S A. 2008;105:16230–5. ArticlePubMedPMC
  • 67. Guil S, Soler M, Portela A, Carrere J, Fonalleras E, Gomez A, et al. Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat Struct Mol Biol. 2012;19:664–70. ArticlePubMed
  • 68. Wang L, Zeng X, Chen S, Ding L, Zhong J, Zhao JC, et al. BRCA1 is a negative modulator of the PRC2 complex. EMBO J. 2013;32:1584–97. ArticlePubMedPMC
  • 69. Kaneko S, Li G, Son J, Xu CF, Margueron R, Neubert TA, et al. Phosphorylation of the PRC2 component Ezh2 is cell cycleregulated and up-regulates its binding to ncRNA. Genes Dev. 2010;24:2615–20. ArticlePubMedPMC
  • 70. da Rocha ST, Boeva V, Escamilla-Del-Arenal M, Ancelin K, Granier C, Matias NR, et al. Jarid2 is implicated in the initial Xist-induced targeting of PRC2 to the inactive X chromosome. Mol Cell. 2014;53:301–16. ArticlePubMed
  • 71. Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, et al. Aktmediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science. 2005;310:306–10. ArticlePubMed
  • 72. Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465–9. ArticlePubMedPMC
  • 73. Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013;23:839–52. ArticlePubMedPMC
  • 74. Sahasrabuddhe AA, Chen X, Chung F, Velusamy T, Lim MS, Elenitoba-Johnson KS. Oncogenic Y641 mutations in EZH2 prevent Jak2/beta-TrCP-mediated degradation. Oncogene. 2014;Jan. 27[Epub]. http://dx.doi.org/10.1038/onc.2013.571Article
  • 75. Chen S, Bohrer LR, Rai AN, Pan Y, Gan L, Zhou X, et al. Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol. 2010;12:1108–14. ArticlePubMedPMC
  • 76. Wu SC, Zhang Y. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability. J Biol Chem. 2011;286:28511–9. ArticlePubMedPMC
  • 77. Wei Y, Chen YH, Li LY, Lang J, Yeh SP, Shi B, et al. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol. 2011;13:87–94. ArticlePubMedPMC
  • 78. Minnebo N, Gornemann J, O'Connell N, Van Dessel N, Derua R, Vermunt MW, et al. NIPP1 maintains EZH2 phosphorylation and promoter occupancy at proliferation-related target genes. Nucleic Acids Res. 2013;41:842–54. ArticlePubMedPMC
  • 79. Li J, Hart RP, Mallimo EM, Swerdel MR, Kusnecov AW, Herrup K. EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia. Nat Neurosci. 2013;16:1745–53. ArticlePubMedPMC
  • 80. Palacios D, Mozzetta C, Consalvi S, Caretti G, Saccone V, Proserpio V, et al. TNF/p38alpha/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell. 2010;7:455–69. ArticlePubMedPMC
  • 81. Chu CS, Lo PW, Yeh YH, Hsu PH, Peng SH, Teng YC, et al. O-GlcNAcylation regulates EZH2 protein stability and function. Proc Natl Acad Sci U S A. 2014;111:1355–60. ArticlePubMedPMC
  • 82. Riising EM, Boggio R, Chiocca S, Helin K, Pasini D. The polycomb repressive complex 2 is a potential target of SUMO modifications. PLoS One. 2008;3:e2704ArticlePubMedPMC
  • 83. Yu YL, Chou RH, Shyu WC, Hsieh SC, Wu CS, Chiang SY, et al. Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke. EMBO Mol Med. 2013;5:531–47. ArticlePubMedPMC
  • 84. Zoabi M, Sadeh R, de Bie P, Marquez VE, Ciechanover A. PRAJA1 is a ubiquitin ligase for the polycomb repressive complex 2 proteins. Biochem Biophys Res Commun. 2011;408:393–8. ArticlePubMed
  • 85. Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13:69–80. ArticlePubMedPMC
  • 86. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181–5. ArticlePubMedPMC
  • 87. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2010;107:20980–5. ArticlePubMedPMC
  • 88. Beguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23:677–92. ArticlePubMedPMC
  • 89. Majer CR, Jin L, Scott MP, Knutson SK, Kuntz KW, Keilhack H, et al. A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS Lett. 2012;586:3448–51. ArticlePubMed
  • 90. McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A. 2012;109:2989–94. ArticlePubMedPMC
  • 91. Lewis PW, Muller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, et al. Inhibition of PRC2 activity by a gain-offunction H3 mutation found in pediatric glioblastoma. Science. 2013;340:857–61. ArticlePubMedPMC
  • 92. Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell. 2013;24:660–72. ArticlePubMed
  • 93. Chan KM, Fang D, Gan H, Hashizume R, Yu C, Schroeder M, et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 2013;27:985–90. ArticlePubMedPMC
  • 94. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006;24:268–73. ArticlePubMed
  • 95. Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ. Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res. 2005;11(24 Pt 1):8570–6. ArticlePubMed
  • 96. Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H. Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci. 2006;97:484–91. ArticlePubMedPMC
  • 97. Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, et al. Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res. 2007;37:974–83. ArticlePubMed
  • 98. Ougolkov AV, Bilim VN, Billadeau DD. Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Cancer Res. 2008;14:6790–6. ArticlePubMedPMC
  • 99. Lee HW, Choe M. Expression of EZH2 in renal cell carcinoma as a novel prognostic marker. Pathol Int. 2012;62:735–41. ArticlePubMed
  • 100. Rao ZY, Cai MY, Yang GF, He LR, Mai SJ, Hua WF, et al. EZH2 supports ovarian carcinoma cell invasion and/or metastasis via regulation of TGF-beta1 and is a predictor of outcome in ovarian carcinoma patients. Carcinogenesis. 2010;31:1576–83. ArticlePubMed
  • 101. Crea F, Hurt EM, Farrar WL. Clinical significance of Polycomb gene expression in brain tumors. Mol Cancer. 2010;9:265.ArticlePubMedPMC
  • 102. Yamada A, Fujii S, Daiko H, Nishimura M, Chiba T, Ochiai A. Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus. Int J Oncol. 2011;38:345–53. ArticlePubMed
  • 103. Behrens C, Solis LM, Lin H, Yuan P, Tang X, Kadara H, et al. EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma. Clin Cancer Res. 2013;19:6556–65. ArticlePubMedPMC
  • 104. Alford SH, Toy K, Merajver SD, Kleer CG. Increased risk for distant metastasis in patients with familial early-stage breast cancer and high EZH2 expression. Breast Cancer Res Treat. 2012;132:429–37. ArticlePubMedPMC
  • 105. Crea F, Hurt EM, Mathews LA, Cabarcas SM, Sun L, Marquez VE, et al. Pharmacologic disruption of Polycomb repressive complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer. 2011;10:40.ArticlePubMedPMC
  • 106. Gonzalez ME, Moore HM, Li X, Toy KA, Huang W, Sabel MS, et al. EZH2 expands breast stem cells through activation of NOTCH1 signaling. Proc Natl Acad Sci U S A. 2014;111:3098–103. ArticlePubMedPMC
  • 107. Li X, Gonzalez ME, Toy K, Filzen T, Merajver SD, Kleer CG. Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia. Am J Pathol. 2009;175:1246–54. ArticlePubMedPMC
  • 108. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665–7. ArticlePubMed
  • 109. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722–6. ArticlePubMed
  • 110. Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, et al. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J Exp Med. 2013;210:2627–39. ArticlePubMedPMC
  • 111. Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med. 2012;18:298–301. ArticlePubMedPMC
  • 112. Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S, et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev. 2012;26:651–6. ArticlePubMedPMC
  • 113. Mallen-St Clair J, Soydaner-Azeloglu R, Lee KE, Taylor L, Livanos A, Pylayeva-Gupta Y, et al. EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev. 2012;26:439–44. ArticlePubMedPMC
  • 114. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007;21:525–30. ArticlePubMedPMC
  • 115. Ezhkova E, Pasolli HA, Parker JS, Stokes N, Su IH, Hannon G, et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009;136:1122–35. ArticlePubMedPMC
  • 116. Reynolds PA, Sigaroudinia M, Zardo G, Wilson MB, Benton GM, Miller CJ, et al. Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem. 2006;281:24790–802. ArticlePubMed
  • 117. Sasaki M, Yamaguchi J, Itatsu K, Ikeda H, Nakanuma Y. Over-expression of polycomb group protein EZH2 relates to decreased expression of p16 INK4a in cholangiocarcinogenesis in hepatolithiasis. J Pathol. 2008;215:175–83. ArticlePubMed
  • 118. Wang C, Liu X, Chen Z, Huang H, Jin Y, Kolokythas A, et al. Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma. Mol Carcinog. 2013;52:229–36. ArticlePubMedPMC
  • 119. Yu H, Simons DL, Segall I, Carcamo-Cavazos V, Schwartz EJ, Yan N, et al. PRC2/EED-EZH2 complex is up-regulated in breast cancer lymph node metastasis compared to primary tumor and correlates with tumor proliferation in situ. PLoS One. 2012;7:e51239ArticlePubMedPMC
  • 120. Fujii S, Ochiai A. Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells. Cancer Sci. 2008;99:738–46. ArticlePubMedPMC
  • 121. Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008;27:7274–84. ArticlePubMedPMC
  • 122. Chen Y, Lin MC, Yao H, Wang H, Zhang AQ, Yu J, et al. Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin. Hepatology. 2007;46:200–8. ArticlePubMed
  • 123. Cheng AS, Lau SS, Chen Y, Kondo Y, Li MS, Feng H, et al. EZH2-mediated concordant repression of Wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011;71:4028–39. ArticlePubMed
  • 124. Yang X, Karuturi RK, Sun F, Aau M, Yu K, Shao R, et al. CDKN1C (p57) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cells. PLoS One. 2009;4:e5011ArticlePubMedPMC
  • 125. Guo J, Cai J, Yu L, Tang H, Chen C, Wang Z. EZH2 regulates expression of p57 and contributes to progression of ovarian cancer in vivo and in vivo. Cancer Sci. 2011;102:530–9. ArticlePubMed
  • 126. Yu J, Cao Q, Yu J, Wu L, Dallol A, Li J, et al. The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer. Oncogene. 2010;29:5370–80. ArticlePubMedPMC
  • 127. Wu L, Runkle C, Jin HJ, Yu J, Li J, Yang X, et al. CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor. Oncogene. 2014;33:504–13. ArticlePubMedPMC
  • 128. Shin YJ, Kim JH. The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells. PLoS One. 2012;7:e30393ArticlePubMedPMC
  • 129. Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, et al. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat Med. 2010;16:286–94. ArticlePubMedPMC
  • 130. Du J, Li L, Ou Z, Kong C, Zhang Y, Dong Z, et al. FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells. Breast Cancer Res Treat. 2012;131:65–73. ArticlePubMed
  • 131. Pathiraja TN, Nayak SR, Xi Y, Jiang S, Garee JP, Edwards DP, et al. Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Sci Transl Med. 2014;6:229ra41.ArticlePubMedPMC
  • 132. Zeidler M, Varambally S, Cao Q, Chinnaiyan AM, Ferguson DO, Merajver SD, et al. The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells. Neoplasia. 2005;7:1011–9. ArticlePubMedPMC
  • 133. Lu H, Sun J, Wang F, Feng L, Ma Y, Shen Q, et al. Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4. Cell Death Dis. 2013;4:e776ArticlePubMedPMC
  • 134. Marchesi I, Fiorentino FP, Rizzolio F, Giordano A, Bagella L. The ablation of EZH2 uncovers its crucial role in rhabdomyosarcoma formation. Cell Cycle. 2012;11:3828–36. ArticlePubMedPMC
  • 135. Wang C, Liu Z, Woo CW, Li Z, Wang L, Wei JS, et al. EZH2 mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR. Cancer Res. 2012;72:315–24. ArticlePubMedPMC
  • 136. Fujii S, Ito K, Ito Y, Ochiai A. Enhancer of zeste homologue 2 (EZH2) down-regulates RUNX3 by increasing histone H3 methylation. J Biol Chem. 2008;283:17324–32. ArticlePubMedPMC
  • 137. Taniguchi H, Jacinto FV, Villanueva A, Fernandez AF, Yamamoto H, Carmona FJ, et al. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene. 2012;31:1988–94. ArticlePubMedPMC
  • 138. Wu ZL, Zheng SS, Li ZM, Qiao YY, Aau MY, Yu Q. Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression. Cell Death Differ. 2010;17:801–10. ArticlePubMed
  • 139. Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21:1050–63. ArticlePubMedPMC
  • 140. De Carvalho DD, Binato R, Pereira WO, Leroy JM, Colassanti MD, Proto-Siqueira R, et al. BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients. Oncogene. 2011;30:223–33. ArticlePubMed
  • 141. Lu C, Han HD, Mangala LS, Ali-Fehmi R, Newton CS, Ozbun L, et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell. 2010;18:185–97. ArticlePubMedPMC
  • 142. Asangani IA, Ateeq B, Cao Q, Dodson L, Pandhi M, Kunju LP, et al. Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. Mol Cell. 2013;49:80–93. ArticlePubMedPMC
  • 143. Cao Q, Mani RS, Ateeq B, Dhanasekaran SM, Asangani IA, Prensner JR, et al. Coordinated regulation of Polycomb group complexes through microRNAs in cancer. Cancer Cell. 2011;20:187–99. ArticlePubMedPMC
  • 144. Shi B, Liang J, Yang X, Wang Y, Zhao Y, Wu H, et al. Integration of estrogen and Wnt signaling circuits by the Polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol. 2007;27:5105–19. ArticlePubMedPMC
  • 145. Jung HY, Jun S, Lee M, Kim HC, Wang X, Ji H, et al. PAF and EZH2 induce Wnt/beta-catenin signaling hyperactivation. Mol Cell. 2013;52:193–205. ArticlePubMedPMC
  • 146. Lee ST, Li Z, Wu Z, Aau M, Guan P, Karuturi RK, et al. Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Mol Cell. 2011;43:798–810. ArticlePubMed
  • 147. Yan J, Ng SB, Tay JL, Lin B, Koh TL, Tan J, et al. EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood. 2013;121:4512–20. ArticlePubMed
  • 148. Lee JM, Lee JS, Kim H, Kim K, Park H, Kim JY, et al. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell. 2012;48:572–86. ArticlePubMed
  • 149. He A, Shen X, Ma Q, Cao J, von Gise A, Zhou P, et al. PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev. 2012;26:37–42. ArticlePubMedPMC
  • 150. Su IH, Dobenecker MW, Dickinson E, Oser M, Basavaraj A, Marqueron R, et al. Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell. 2005;121:425–36. ArticlePubMed
  • 151. Bryant RJ, Winder SJ, Cross SS, Hamdy FC, Cunliffe VT. The Polycomb group protein EZH2 regulates actin polymerization in human prostate cancer cells. Prostate. 2008;68:255–63. ArticlePubMed
  • 152. Campbell S, Ismail IH, Young LC, Poirier GG, Hendzel MJ. Polycomb repressive complex 2 contributes to DNA doublestrand break repair. Cell Cycle. 2013;12:2675–83. ArticlePubMedPMC
  • 153. Gonzalez ME, Li X, Toy K, DuPrie M, Ventura AC, Banerjee M, et al. Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1. Oncogene. 2009;28:843–53. ArticlePubMedPMC
  • 154. Gonzalez ME, DuPrie ML, Krueger H, Merajver SD, Ventura AC, Toy KA, et al. Histone methyltransferase EZH2 induces Akt-dependent genomic instability and BRCA1 inhibition in breast cancer. Cancer Res. 2011;71:2360–70. ArticlePubMedPMC
  • 155. Puppe J, Drost R, Liu X, Joosse SA, Evers B, Cornelissen-Steijger P, et al. BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb repressive complex 2-inhibitor 3-deazaneplanocin A. Breast Cancer Res. 2009;11:R63.ArticlePubMedPMC
  • 156. Alimova I, Venkataraman S, Harris P, Marquez VE, Northcott PA, Dubuc A, et al. Targeting the enhancer of zeste homologue 2 in medulloblastoma. Int J Cancer. 2012;131:1800–9. ArticlePubMedPMC
  • 157. Kemp CD, Rao M, Xi S, Inchauste S, Mani H, Fetsch P, et al. Polycomb repressor complex-2 is a novel target for mesothelioma therapy. Clin Cancer Res. 2012;18:77–90. ArticlePubMed
  • 158. Kalushkova A, Fryknas M, Lemaire M, Fristedt C, Agarwal P, Eriksson M, et al. Polycomb target genes are silenced in multiple myeloma. PLoS One. 2010;5:e11483ArticlePubMedPMC
  • 159. Gannon OM, Merida de Long L, Endo-Munoz L, Hazar-Rethinam M, Saunders NA. Dysregulation of the repressive H3K27 trimethylation mark in head and neck squamous cell carcinoma contributes to dysregulated squamous differentiation. Clin Cancer Res. 2013;19:428–41. ArticlePubMed
  • 160. Fujiwara T, Saitoh H, Inoue A, Kobayashi M, Okitsu Y, Katsuoka Y, et al. 3-Deazaneplanocin A (DZNep), an inhibitor of S-adenosylmethionine-dependent methyltransferase, promotes erythroid differentiation. J Biol Chem. 2014;289:8121–34. ArticlePubMedPMC
  • 161. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12. ArticlePubMed
  • 162. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8:890–6. ArticlePubMed
  • 163. Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014;13:842–54. ArticlePubMed
  • 164. Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012;109:21360–5. ArticlePubMedPMC
  • 165. Hua WF, Fu YS, Liao YJ, Xia WJ, Chen YC, Zeng YX, et al. Curcumin induces down-regulation of EZH2 expression through the MAPK pathway in MDA-MB-435 human breast cancer cells. Eur J Pharmacol. 2010;637:16–21. ArticlePubMed
  • 166. Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS, et al. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 2012;72:335–45. ArticlePubMedPMC
  • 167. Dimri M, Bommi PV, Sahasrabuddhe AA, Khandekar JD, Dimri GP. Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells. Carcinogenesis. 2010;31:489–95. ArticlePubMedPMC
  • 168. Wang S, Zhu Y, He H, Liu J, Xu L, Zhang H, et al. Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog 2. Cancer Sci. 2013;104:750–9. ArticlePubMedPMC
  • 169. Avan A, Crea F, Paolicchi E, Funel N, Galvani E, Marquez VE, et al. Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells. Mol Cancer Ther. 2012;11:1735–46. ArticlePubMedPMC
  • 170. Fiskus W, Rao R, Balusu R, Ganguly S, Tao J, Sotomayor E, et al. Superior efficacy of a combined epigenetic therapy against human mantle cell lymphoma cells. Clin Cancer Res. 2012;18:6227–38. ArticlePubMedPMC
  • 171. Hayden A, Johnson PW, Packham G, Crabb SJ. S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition. Breast Cancer Res Treat. 2011;127:109–19. ArticlePubMed
  • 172. Sun F, Chan E, Wu Z, Yang X, Marquez VE, Yu Q. Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells. Mol Cancer Ther. 2009;8:3191–202. ArticlePubMedPMC
  • 173. Lv Y, Yuan C, Xiao X, Wang X, Ji X, Yu H, et al. The expression and significance of the enhancer of zeste homolog 2 in lung adenocarcinoma. Oncol Rep. 2012;28:147–54. ArticlePubMed
  • 174. Hu S, Yu L, Li Z, Shen Y, Wang J, Cai J, et al. Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vivo and in vivo. Cancer Biol Ther. 2010;10:788–95. ArticlePubMed

Figure & Data

REFERENCES

    Citations

    Citations to this article as recorded by  
    • Conformationally constrained potent inhibitors for enhancer of zeste homolog 2 (EZH2)
      Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
      Bioorganic & Medicinal Chemistry Letters.2024; 97: 129558.     CrossRef
    • Development of a Cost-Efficient Process Toward a Key Synthetic Intermediate of the EZH2 Inhibitor PF-06821497
      Christopher P. Ashcroft, Alexander M. Berne, Florian Blasberg, Kelly Catlin, Michael R. Collins, Doug J. Critcher, Jean-Nicolas Desrosiers, Adam Goetz, Cheryl Hayward, Ricky A. Jones, Michael J. Karmilowicz, Nandell Keene, Carlos A. Martinez, Sebastien Mo
      Organic Process Research & Development.2024; 28(6): 2260.     CrossRef
    • MicroRNAs and long non-coding RNAs during transcriptional regulation and latency of HIV and HTLV
      Sergio P. Alpuche-Lazcano, Robert J. Scarborough, Anne Gatignol
      Retrovirology.2024;[Epub]     CrossRef
    • Nuclear Biophysical Changes during Human Melanoma Plasticity
      Maria Chiara Lionetti, Maria Rita Fumagalli, Caterina A.M. La Porta
      Cells Tissues Organs.2024; 213(2): 120.     CrossRef
    • The Role of H3K27me3-Mediated Th17 Differentiation in Ankylosing Spondylitis
      Yuening Chen, Wanlin Liu, Xiaohan Xu, Hongying Zhen, Bo Pang, Zhe Zhao, Yanan Zhao, Hongxiao Liu
      Inflammation.2024; 47(5): 1685.     CrossRef
    • O‐GlcNAc regulates anti‐fibrotic genes in lung fibroblasts through EZH2
      Qiuming P. Wu, Shia Vang, Jennifer Q. Zhou, Stefanie Krick, Jarrod W. Barnes, Yan Y. Sanders
      Journal of Cellular and Molecular Medicine.2024;[Epub]     CrossRef
    • A Case of SMARCB1-Deficient Sinonasal Carcinoma With Clear Cell Morphology
      Tomoko Tamaki, Kyonosuke Teruya, Hitoshi Hirakawa, Mariko Tomita, Naoki Wada
      Cureus.2024;[Epub]     CrossRef
    • Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST
      Dayong Zheng, Yan Zhang, Sukjin Yang, Ning Su, Michael Bakhoum, Guoliang Zhang, Samira Naderinezhad, Zhengmei Mao, Zheng Wang, Ting Zhou, Wenliang Li
      Cell Death Discovery.2024;[Epub]     CrossRef
    • EZH2‐associated tumor malignancy: A prominent target for cancer treatment
      Maryam Sabour‐Takanlou, Leila Sabour‐Takanlou, Cigir Biray‐Avci
      Clinical Genetics.2024; 106(4): 377.     CrossRef
    • Targeting IL-11R/EZH2 signaling axis as a therapeutic strategy for osteosarcoma lung metastases
      Eswaran Devarajan, R. Eric Davis, Hannah C. Beird, Wei-Lien Wang, V. Behrana Jensen, Arumugam Jayakumar, Cheuk Hong Leung, Heather Y. Lin, Chia-Chin Wu, Stephanie A. Ihezie, Jen-Wei Tsai, P. Andrew Futreal, Valerae O. Lewis
      Discover Oncology.2024;[Epub]     CrossRef
    • Bisphenol S (BPS) induces glioblastoma progression via regulation of EZH2-mediated PI3K/AKT/mTOR pathway in U87-MG cells
      Moon Yi Ko, Heejin Park, Younhee Kim, Euijun Min, Sin-Woo Cha, Byoung-Seok Lee, Sung-Ae Hyun, Minhan Ka
      Toxicology.2024; 507: 153898.     CrossRef
    • SWI/SNF-Related Matrix-Associated Actin-Dependent Regulator of Chromatin Subfamily B Member 1 (SMARCB1)-Deficient Tumor in the Parapharyngeal Space: A Case Report
      Seiichiro Kamimura, Eiji Kondo, Takahiro Azuma, Go Sato, Yoshiaki Kitamura
      Cureus.2024;[Epub]     CrossRef
    • H3K27me3 Loss in Central Nervous System Tumors: Diagnostic, Prognostic, and Therapeutic Implications
      Giuseppe Angelico, Manuel Mazzucchelli, Giulio Attanasio, Giordana Tinnirello, Jessica Farina, Magda Zanelli, Andrea Palicelli, Alessandra Bisagni, Giuseppe Maria Vincenzo Barbagallo, Francesco Certo, Maurizio Zizzo, Nektarios Koufopoulos, Gaetano Magro,
      Cancers.2024; 16(20): 3451.     CrossRef
    • A study of the diagnostic and prognostic role of enhancer of zeste homolog 2 and BRCA1-associated protein 1 expression in different prostatic lesions (an immunohistochemical study)
      Samah I. Saleh, Amira E. Soliman, Mona A. Aboelkheir
      Egyptian Journal of Pathology.2024; 44(1): 48.     CrossRef
    • EZH2 Activates HTLV‐1 bZIP Factor‐Mediated TGF‐β Signaling in Adult T‐Cell Leukemia
      Xu Zhang, Kaining Yi, Bingbing Wang, Kaifei Chu, Jie Liu, Jie Zhang, Jiaqi Fang, Tiejun Zhao
      Journal of Medical Virology.2024;[Epub]     CrossRef
    • CRISPR/Cas9-based genome editing for multimodal synergistic cancer nanotherapy
      Yinying Pu, Wencheng Wu, Huijing Xiang, Yu Chen, Huixiong Xu
      Nano Today.2023; 48: 101734.     CrossRef
    • EZH2/hSULF1 axis mediates receptor tyrosine kinase signaling to shape cartilage tumor progression
      Zong-Shin Lin, Chiao-Chen Chung, Yu-Chia Liu, Chu-Han Chang, Hui-Chia Liu, Yung-Yi Liang, Teng-Le Huang, Tsung-Ming Chen, Che-Hsin Lee, Chih-Hsin Tang, Mien-Chie Hung, Ya-Huey Chen
      eLife.2023;[Epub]     CrossRef
    • Discovery of IHMT-337 as a potent irreversible EZH2 inhibitor targeting CDK4 transcription for malignancies
      Husheng Mei, Hong Wu, Jing Yang, Bin Zhou, Aoli Wang, Chen Hu, Shuang Qi, Zongru Jiang, Fengming Zou, Beilei Wang, Feiyang Liu, Yongfei Chen, Wenchao Wang, Jing Liu, Qingsong Liu
      Signal Transduction and Targeted Therapy.2023;[Epub]     CrossRef
    • SMARCB1(INI-1)-Deficient Sinonasal Carcinoma: An Evolving Entity
      Sei Y. Chung, Parker Kenee, Tanner Mitton, Ashleigh Halderman
      Journal of Neurological Surgery Reports.2023; 84(01): e1.     CrossRef
    • Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma
      Anne Uebel, Stefanie Kewitz-Hempel, Edith Willscher, Kathleen Gebhardt, Cord Sunderkötter, Dennis Gerloff
      International Journal of Molecular Sciences.2023; 24(3): 1963.     CrossRef
    • miRNA let-7a inhibits invasion, migration, anchorage-independent growth by suppressing EZH2 and promotes mesenchymal to epithelial transition in MDAMB-231
      Nibedita Patel, Koteswara Rao Garikapati, Venkata Krishna Kanth Makani, Shreya Pal, Namratha Vangara, Manika Pal Bhadra
      Gene Reports.2023; 31: 101752.     CrossRef
    • Inhibition of EZH2 exerts antitumorigenic effects in renal cell carcinoma via LATS1
      Seong Hwi Hong, Hyun Ji Hwang, Da Hyeon Son, Eun Song Kim, Sung Yul Park, Young Eun Yoon
      FEBS Open Bio.2023; 13(4): 724.     CrossRef
    • Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells
      Y. Sbirkov, T. Schenk, C. Kwok, S. Stengel, R. Brown, G. Brown, L. Chesler, A. Zelent, M. J. Fuchter, K. Petrie
      Frontiers in Cell and Developmental Biology.2023;[Epub]     CrossRef
    • Dual role of enhancer of zeste homolog 2 in the regulation of ultraviolet radiation-induced matrix metalloproteinase-1 and type I procollagen expression in human dermal fibroblasts
      Min-Kyoung Kim, Hye Sun Shin, Mi Hee Shin, Haesoo Kim, Dong Hun Lee, Jin Ho Chung
      Matrix Biology.2023; 119: 112.     CrossRef
    • A patent review of EZH2 inhibitors from 2017 and beyond
      Guoquan Wan, Huan Feng, Chang Su, Yongxia Zhu, Lidan Zhang, Qiangsheng Zhang, Luoting Yu
      Expert Opinion on Therapeutic Patents.2023; 33(4): 293.     CrossRef
    • Epigenetic effects of herbal medicine
      Yu-Yao Wu, Yan-Ming Xu, Andy T. Y. Lau
      Clinical Epigenetics.2023;[Epub]     CrossRef
    • Lysophosphatidic Acid Induces Podocyte Pyroptosis in Diabetic Nephropathy by an Increase of Egr1 Expression via Downregulation of EzH2
      Donghee Kim, Ka-Yun Ban, Geon-Ho Lee, Hee-Sook Jun
      International Journal of Molecular Sciences.2023; 24(12): 9968.     CrossRef
    • SMARCB1‐deficient basal cell carcinoma of the prostate controlled using radiation therapy
      Shunta Makabe, Tomoyuki Koguchi, Kanako Matsuoka, Seiji Hoshi, Junya Hata, Yuichi Sato, Hidenori Akaihata, Masao Kataoka, Motohide Uemura, Yoshiyuki Kojima
      IJU Case Reports.2023; 6(4): 248.     CrossRef
    • JARID2 and EZH2, the eminent epigenetic drivers in human cancer
      Bhuvanadas Sreeshma, Arikketh Devi
      Gene.2023; 879: 147584.     CrossRef
    • Design, synthesis and mechanism studies of dual EZH2/BRD4 inhibitors for cancer therapy
      Xinye Chen, Cheng Wang, Dehua Lu, Heng Luo, Shang Li, Fucheng Yin, Zhongwen Luo, Ningjie Cui, Lingyi Kong, Xiaobing Wang
      Bioorganic & Medicinal Chemistry.2023; 91: 117386.     CrossRef
    • Review: Targeting EZH2 in neuroblastoma
      Jinhui Gao, Claire Fosbrook, Jane Gibson, Timothy J. Underwood, Juliet C. Gray, Zoë S. Walters
      Cancer Treatment Reviews.2023; 119: 102600.     CrossRef
    • Integrative Multi-Omics Analysis of Oncogenic EZH2 Mutants: From Epigenetic Reprogramming to Molecular Signatures
      Julian Aldana, Miranda L. Gardner, Michael A. Freitas
      International Journal of Molecular Sciences.2023; 24(14): 11378.     CrossRef
    • The Role of EZH2 in Ocular Diseases: A Narrative Review
      Yu Peng, Christine HT Bui, Xiu J Zhang, Jian S Chen, Clement C Tham, Wai K Chu, Li J Chen, Chi P Pang, Jason C Yam
      Epigenomics.2023; 15(9): 557.     CrossRef
    • Targeting EZH2 in SMARCB1-deficient sarcomas: Advances and opportunities to potentiate the efficacy of EZH2 inhibitors
      Cinzia Lanzi, Noemi Arrighetti, Sandro Pasquali, Giuliana Cassinelli
      Biochemical Pharmacology.2023; 215: 115727.     CrossRef
    • EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis
      Chen-Shiou Wu, Yi-Chung Chien, Chia‐Jui Yen, Jia-Yan Wu, Li-Yuan Bai, Yung-Luen Yu
      Cancer Cell International.2023;[Epub]     CrossRef
    • SUZ12 inhibition attenuates cell proliferation of glioblastoma via post-translational regulation of CDKN1B
      Sojin Kim, Sungsin Jo, Sun Ha Paek, Sang Soo Kang, Heekyoung Chung
      Genes & Genomics.2023; 45(12): 1623.     CrossRef
    • Non-Coding RNA in Cholangiocarcinoma: An Update
      Jiehan Li, Haolin Bao, Ziyue Huang, Zixin Liang, Ning Lin, Chunjie Ni, Yi Xu
      Frontiers in Bioscience-Landmark.2023;[Epub]     CrossRef
    • Advances in neuroendocrine prostate cancer research: From model construction to molecular network analyses
      Xue Shui, Rong Xu, Caiqin Zhang, Han Meng, Jumei Zhao, Changhong Shi
      Laboratory Investigation.2022; 102(4): 332.     CrossRef
    • MicroRNA-217: a therapeutic and diagnostic tumor marker
      Amir Abbas Hamidi, Malihe Zangoue, Daniel Kashani, Amir Sadra Zangouei, Hamid Reza Rahimi, Mohammad Reza Abbaszadegan, Meysam Moghbeli
      Expert Review of Molecular Diagnostics.2022; 22(1): 61.     CrossRef
    • Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2
      Jing Yang, Ellen L. Weisberg, Shuang Qi, Wei Ni, Husheng Mei, Zuowei Wang, Chengcheng Meng, Shengzhe Zhang, Mingqi Hou, Ziping Qi, Aoli Wang, Yunyun Jiang, Zongru Jiang, Tao Huang, Qingwang Liu, Robert S. Magin, Laura Doherty, Wenchao Wang, Jing Liu, Sara
      Leukemia.2022; 36(4): 1048.     CrossRef
    • Mechanisms of Polycomb group protein function in cancer
      Victoria Parreno, Anne-Marie Martinez, Giacomo Cavalli
      Cell Research.2022; 32(3): 231.     CrossRef
    • Clinical Diagnosis and Treatment Analyses on SMARCB1 (Integrase Interactor 1)–Deficient Sinonasal Carcinoma: Case Series with Systematic Review of the Literature
      Ru Wang, Lingwa Wang, Jugao Fang, Qi Zhong, Lizhen Hou, Hongzhi Ma, Ling Feng, Shizhi He, Chengshuo Wang, Luo Zhang
      World Neurosurgery.2022; 161: e229.     CrossRef
    • EZH2 Protein Expression in Triple-negative Breast Cancer Treated With Neoadjuvant Chemotherapy: An Exploratory Study of Association With Tumor Response and Prognosis
      Susan Fineberg, Xuejun Tian, Della Makower, Malini Harigopal, Yungtai Lo
      Applied Immunohistochemistry & Molecular Morphology.2022; 30(3): 157.     CrossRef
    • Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma
      Matthew L. Hedberg, Corbett T. Berry, Ata S. Moshiri, Yan Xiang, Christopher J. Yeh, Cem Attilasoy, Brian C. Capell, John T. Seykora
      International Journal of Molecular Sciences.2022; 23(7): 3478.     CrossRef
    • Identification of SET/EED Dual Binders As Innovative PRC2 Inhibitors
      Raffaella Catalano, Annalisa Maruca, Roberta Rocca, Pierfrancesco Tassone, Giulia Panzarella, Giosuè Costa, Francesco Ortuso, Stefano Alcaro
      Future Medicinal Chemistry.2022; 14(9): 609.     CrossRef
    • METTL3 Accelerates Breast Cancer Progression via Regulating EZH2 m6A Modification
      Shaojun Hu, Yang Song, Yu Zhou, Yu Jiao, Guopeng Li, Deepak Kumar Jain
      Journal of Healthcare Engineering.2022; 2022: 1.     CrossRef
    • IGF2BP1 Promotes Proliferation of Neuroendocrine Neoplasms by Post-Transcriptional Enhancement of EZH2
      Florian Sperling, Danny Misiak, Stefan Hüttelmaier, Patrick Michl, Heidi Griesmann
      Cancers.2022; 14(9): 2121.     CrossRef
    • KDM2B mediates the Wnt/β-catenin pathway through transcriptional activation of PKMYT1 via microRNA-let-7b-5p/EZH2 to affect the development of non-small cell lung cancer
      Xuedong Zhang, Zhongbo Yin, Chuanyi Li, Lishen Nie, Keyan Chen
      Experimental Cell Research.2022; 417(2): 113208.     CrossRef
    • Loss of H3K27 Trimethylation Promotes Radiotherapy Resistance in Medulloblastoma and Induces an Actionable Vulnerability to BET Inhibition
      Nishanth Gabriel, Kumaresh Balaji, Kay Jayachandran, Matthew Inkman, Jin Zhang, Sonika Dahiya, Michael Goldstein
      Cancer Research.2022; 82(10): 2019.     CrossRef
    • Pharmacologic Induction of BRCAness in BRCA-Proficient Cancers: Expanding PARP Inhibitor Use
      Rachel Abbotts, Anna J. Dellomo, Feyruz V. Rassool
      Cancers.2022; 14(11): 2640.     CrossRef
    • Targeting EZH2 to overcome the resistance to immunotherapy in lung cancer
      Daniel Sanghoon Shin, Kevin Park, Edward Garon, Steven Dubinett
      Seminars in Oncology.2022; 49(3-4): 306.     CrossRef
    • SMARCB1 (INI-1)-Deficient Sinonasal Carcinoma: A Systematic Review and Pooled Analysis of Treatment Outcomes
      Victor Ho-Fun Lee, Raymond King-Yin Tsang, Anthony Wing Ip Lo, Sum-Yin Chan, Joseph Chun-Kit Chung, Chi-Chung Tong, To-Wai Leung, Dora Lai-Wan Kwong
      Cancers.2022; 14(13): 3285.     CrossRef
    • Degradable polyprodrugs: design and therapeutic efficiency
      Farzad Seidi, Yajie Zhong, Huining Xiao, Yongcan Jin, Daniel Crespy
      Chemical Society Reviews.2022; 51(15): 6652.     CrossRef
    • PAR-Induced Harnessing of EZH2 to β-Catenin: Implications for Colorectal Cancer
      Shoshana Sedley, Jeetendra Kumar Nag, Tatyana Rudina, Rachel Bar-Shavit
      International Journal of Molecular Sciences.2022; 23(15): 8758.     CrossRef
    • Insight into Thermodynamic and Kinetic Profiles in Small-Molecule Optimization
      Wei Liu, Jingsheng Jiang, Yating Lin, Qidong You, Lei Wang
      Journal of Medicinal Chemistry.2022; 65(16): 10809.     CrossRef
    • EZH2 Protein Expression in Estrogen Receptor Positive Invasive Breast Cancer Treated With Neoadjuvant Endocrine Therapy: An Exploratory Study of Association With Tumor Response
      Yujun Gan, Yungtai Lo, Della Makower, Celina Kleer, Jinyu Lu, Susan Fineberg
      Applied Immunohistochemistry & Molecular Morphology.2022; 30(9): 614.     CrossRef
    • Histone Deacetylase and Enhancer of Zeste Homologue 2 Dual Inhibitors Presenting a Synergistic Effect for the Treatment of Hematological Malignancies
      Dehua Lu, Cheng Wang, Lailiang Qu, Fucheng Yin, Shang Li, Heng Luo, Yonglei Zhang, Xingchen Liu, Xinye Chen, Zhongwen Luo, Ningjie Cui, Lingyi Kong, Xiaobing Wang
      Journal of Medicinal Chemistry.2022; 65(19): 12838.     CrossRef
    • EZH2 Inhibition and Cisplatin as a Combination Anticancer Therapy: An Overview of Preclinical Studies
      Ivana Samaržija, Marko Tomljanović, Renata Novak Kujundžić, Koraljka Gall Trošelj
      Cancers.2022; 14(19): 4761.     CrossRef
    • The role of transcription factors in the acquisition of the four latest proposed hallmarks of cancer and corresponding enabling characteristics
      Maria P. Morgan, Ellen Finnegan, Sudipto Das
      Seminars in Cancer Biology.2022; 86: 1203.     CrossRef
    • EZH2 Promotes Cholangiocarcinoma Development and Progression through Histone Methylation and microRNA-Mediated Down-Regulation of Tumor Suppressor Genes
      Jinqiang Zhang, Weina Chen, Wenbo Ma, Chang Han, Kyoungsub Song, Hyunjoo Kwon, Tong Wu
      The American Journal of Pathology.2022; 192(12): 1712.     CrossRef
    • Distinct binding pattern of EZH2 and JARID2 on RNAs and DNAs in hepatocellular carcinoma development
      Zhili Wen, Ke He, Meixiao Zhan, Yong Li, Fei Liu, Xu He, Yanli Wei, Wei Zhao, Yu Zhang, Yaqiang Xue, Yong Xia, Fenfen Wang, Zhenglin Xia, Yongjie Xin, Yeye Wu, Xiaopeng Duan, Jing Xiao, Feng Shen, Yuliang Feng, Guoan Xiang, Ligong Lu
      Frontiers in Oncology.2022;[Epub]     CrossRef
    • Dynamic‐shared Pharmacophore Approach as Tool to Design New Allosteric PRC2 Inhibitors, Targeting EED Binding Pocket
      Jessica Lombino, Maria Rita Gulotta, Giada De Simone, Nedra Mekni, Maria De Rosa, Daniela Carbone, Barbara Parrino, Stella Maria Cascioferro, Patrizia Diana, Alessandro Padova, Ugo Perricone
      Molecular Informatics.2021;[Epub]     CrossRef
    • Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance synergistic cancer therapy
      Qingfei Zhang, Gaizhen Kuang, Shasha He, Sha Liu, Hongtong Lu, Xiaoyuan Li, Dongfang Zhou, Yubin Huang
      Nano Research.2021; 14(3): 601.     CrossRef
    • Elevated EZH2 in ischemic heart disease epigenetically mediates suppression of NaV1.5 expression
      Limei Zhao, Tao You, Yan Lu, Shin Lin, Faqian Li, Haodong Xu
      Journal of Molecular and Cellular Cardiology.2021; 153: 95.     CrossRef
    • Taxanes in cancer treatment: Activity, chemoresistance and its overcoming
      Luciana Mosca, Andrea Ilari, Francesco Fazi, Yehuda G. Assaraf, Gianni Colotti
      Drug Resistance Updates.2021; 54: 100742.     CrossRef
    • MicroRNAs Involved in Inflammatory Breast Cancer: Oncogene and Tumor Suppressors with Possible Targets
      Zohreh Rezaei, Farzad Sadri
      DNA and Cell Biology.2021; 40(3): 499.     CrossRef
    • Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation
      Karolina Pyziak, Agnieszka Sroka‐Porada, Tomasz Rzymski, Józef Dulak, Agnieszka Łoboda
      Drug Development Research.2021; 82(6): 730.     CrossRef
    • The noncanonical role of EZH2 in cancer
      Jinhua Huang, Hongwei Gou, Jia Yao, Kaining Yi, Zhigang Jin, Masao Matsuoka, Tiejun Zhao
      Cancer Science.2021; 112(4): 1376.     CrossRef
    • RePhine: An Integrative Method for Identification of Drug Response-Related Transcriptional Regulators
      Xujun Wang, Zhengtao Zhang, Wenyi Qin, Shiyi Liu, Cong Liu, Georgi Z. Genchev, Lijian Hui, Hongyu Zhao, Hui Lu
      Genomics, Proteomics & Bioinformatics.2021; 19(4): 534.     CrossRef
    • Diagnostic Utility of BAP1, EZH2 and Survivin in Differentiating Pleural Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia: Immunohistochemical Study
      Sarah Adel Hakim, Hoda Hassan Abou Gabal
      Pathology and Oncology Research.2021;[Epub]     CrossRef
    • Clinical and Genomic Characteristics of Adult Diffuse Midline Glioma
      Changhee Park, Tae Min Kim, Jeong Mo Bae, Hongseok Yun, Jin Wook Kim, Seung Hong Choi, Soon-Tae Lee, Joo Ho Lee, Sung-Hye Park, Chul-Kee Park
      Cancer Research and Treatment.2021; 53(2): 389.     CrossRef
    • Epigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer
      Alba Loras, Cristina Segovia, José Luis Ruiz-Cerdá
      Cancers.2021; 13(11): 2719.     CrossRef
    • The Biological Function, Mechanism, and Clinical Significance of m6A RNA Modifications in Head and Neck Carcinoma: A Systematic Review
      Feng-Yang Jing, Li-Ming Zhou, Yu-Jie Ning, Xiao-Juan Wang, You-Ming Zhu
      Frontiers in Cell and Developmental Biology.2021;[Epub]     CrossRef
    • Clinical Perspectives to Overcome Acquired Resistance to Anti–Programmed Death-1 and Anti–Programmed Death Ligand-1 Therapy in Non-Small Cell Lung Cancer
      Yong Jun Lee, Jii Bum Lee, Sang-Jun Ha, Hye Ryun Kim
      Molecules and Cells.2021; 44(5): 363.     CrossRef
    • Horizontal transfer of the stemness-related markers EZH2 and GLI1 by neuroblastoma-derived extracellular vesicles in stromal cells
      Aranzazu Villasante, Amandine Godier-Furnemont, Alberto Hernandez-Barranco, Johanne Le Coq, Jasminka Boskovic, Hector Peinado, Jaume Mora, Josep Samitier, Gordana Vunjak-Novakovic
      Translational Research.2021; 237: 82.     CrossRef
    • PBDEs affect inflammatory and oncosuppressive mechanisms via the EZH2 methyltransferase in airway epithelial cells
      Giulia Anzalone, Monica Moscato, Angela Marina Montalbano, Giusy Daniela Albano, Rosalia Gagliardo, Roberto Marchese, Alberto Fucarino, Chiara Lo Nigro, Gaspare Drago, Mirella Profita
      Life Sciences.2021; 282: 119827.     CrossRef
    • Overexpression of miR-378 Alleviates Chronic Sciatic Nerve Injury by Targeting EZH2
      Pengfei Gao, Xin Zeng, Lin Zhang, Long Wang, Lu-Lu Shen, Ya-Yun Hou, Fang Zhou, Xianlong Zhang
      Neurochemical Research.2021; 46(12): 3213.     CrossRef
    • Involvement of EZH2 inhibition in lenalidomide and pomalidomide-mediated growth suppression in HTLV-1-infected cells
      Nobuyo Kondo, Yoshiko Nagano, Atsuhiko Hasegawa, Miku Ishizawa, Kuniko Katagiri, Takeru Yoneda, Takao Masuda, Mari Kannagi
      Biochemical and Biophysical Research Communications.2021; 574: 104.     CrossRef
    • Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas
      Bin Zhou, Xiaofei Liang, Husheng Mei, Shuang Qi, Zongru Jiang, Aoli Wang, Fengming Zou, Qingwang Liu, Juan Liu, Wenliang Wang, Chen Hu, Yongfei Chen, Zuowei Wang, Beilei Wang, Li Wang, Jing Liu, Qingsong Liu
      Journal of Medicinal Chemistry.2021; 64(20): 15170.     CrossRef
    • EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma
      Yuko Kusakabe, Tetsuhiro Chiba, Motohiko Oshima, Shuhei Koide, Ola Rizq, Kazumasa Aoyama, Junjie Ao, Tatsuya Kaneko, Hiroaki Kanzaki, Kengo Kanayama, Takahiro Maeda, Tomoko Saito, Ryo Nakagawa, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Sadahis
      Scientific Reports.2021;[Epub]     CrossRef
    • Histone Demethylase UTX/KDM6A Regulates Glioblastoma Progression Through Modulating the Tumor Microenvironment
      Yan Luan, Yingfei Liu, Jingwen Xue, Ke Wang, Kaige Ma, Xinlin Chen, Zhichao Zhang, Yong Liu
      SSRN Electronic Journal .2021;[Epub]     CrossRef
    • LncRNA-ANCR down-regulation suppresses invasion and migration of colorectal cancer cells by regulating EZH2 expression
      Zhao-Yang Yang, Fang Yang, Ying-Li Zhang, Bao Liu, Meng Wang, Xuan Hong, Yan Yu, Yao-Hui Zhou, Hai Zeng
      Cancer Biomarkers.2020; 18(1): 95.     CrossRef
    • Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway
      Huanan Wang, Yeying Liu, Jie Ding, Yuan Huang, Jing Liu, Nannan Liu, Yue Ao, Yi Hong, Lefeng Wang, Lingling Zhang, Jiangang Wang, Yingjie Zhang
      Cancer Gene Therapy.2020; 27(6): 448.     CrossRef
    • Utility of histone H3K27me3 and H4K20me as diagnostic indicators of melanoma
      Lauren E. Davis, Sara C. Shalin, Alan J. Tackett
      Melanoma Research.2020; 30(2): 159.     CrossRef
    • Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis
      Yingfeng Shi, Min Tao, Yi Wang, Xiujuan Zang, Xiaoyan Ma, Andong Qiu, Shougang Zhuang, Na Liu
      The Journal of Pathology.2020; 250(1): 79.     CrossRef
    • Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer
      Shira Yomtoubian, Sharrell B. Lee, Akanksha Verma, Franco Izzo, Geoffrey Markowitz, Hyejin Choi, Leandro Cerchietti, Linda Vahdat, Kristy A. Brown, Eleni Andreopoulou, Olivier Elemento, Jenny Chang, Giorgio Inghirami, Dingcheng Gao, Seongho Ryu, Vivek Mit
      Cell Reports.2020; 30(3): 755.     CrossRef
    • HOXC10 promotes cell migration, invasion, and tumor growth in gastric carcinoma cells through upregulating proinflammatory cytokines
      Jingzhang Li, Gangling Tong, Cheng Huang, Yunsheng Luo, Shubin Wang, Ying Zhang, Boran Cheng, Zhihong Zhang, Xuan Wu, Qiumei Liu, Min Li, Laiqing Li, Bingqiang Ni
      Journal of Cellular Physiology.2020; 235(4): 3579.     CrossRef
    • A TGF-β-MTA1-SOX4-EZH2 signaling axis drives epithelial–mesenchymal transition in tumor metastasis
      Lina Li, Jian Liu, Hongsheng Xue, Chunxiao Li, Qun Liu, Yantong Zhou, Ting Wang, Haijuan Wang, Haili Qian, Tao Wen
      Oncogene.2020; 39(10): 2125.     CrossRef
    • Network-Based Genetic Profiling Reveals Cellular Pathway Differences Between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma
      Md. Ali Hossain, Tania Akter Asa, Md. Mijanur Rahman, Shahadat Uddin, Ahmed A. Moustafa, Julian M. W. Quinn, Mohammad Ali Moni
      International Journal of Environmental Research and Public Health.2020; 17(4): 1373.     CrossRef
    • Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time
      Avinash Khanna, Alexandre Côté, Shilpi Arora, Ludivine Moine, Victor S. Gehling, Jehrod Brenneman, Nico Cantone, Jacob I. Stuckey, Shruti Apte, Ashwin Ramakrishnan, Kamil Bruderek, William D. Bradley, James E. Audia, Richard T. Cummings, Robert J. Sims, P
      ACS Medicinal Chemistry Letters.2020; 11(6): 1205.     CrossRef
    • Cancer Stem Cell Plasticity – A Deadly Deal
      Archana P. Thankamony, Kritika Saxena, Reshma Murali, Mohit Kumar Jolly, Radhika Nair
      Frontiers in Molecular Biosciences.2020;[Epub]     CrossRef
    • Acquired resistance to DZNep-mediated apoptosis is associated with copy number gains of AHCY in a B-cell lymphoma model
      Chidimma Agatha Akpa, Karsten Kleo, Elisabeth Oker, Nancy Tomaszewski, Clemens Messerschmidt, Cristina López, Rabea Wagener, Kathrin Oehl-Huber, Katja Dettmer, Anne Schoeler, Dido Lenze, Peter J. Oefner, Dieter Beule, Reiner Siebert, David Capper, Lora Di
      BMC Cancer.2020;[Epub]     CrossRef
    • Long noncoding RNA ANRIL promotes the malignant progression of cholangiocarcinoma by epigenetically repressing ERRFI1 expression
      Yang Yu, Qiaoyu Chen, Xunlei Zhang, Jian Yang, Kaibo Lin, Congfei Ji, Aibing Xu, Lei Yang, Lin Miao
      Cancer Science.2020; 111(7): 2297.     CrossRef
    • CAMK2A supported tumor initiating cells of lung adenocarcinoma by upregulating SOX2 through EZH2 phosphorylation
      Si-Qi Wang, Jing Liu, Jing Qin, Yun Zhu, Vicky Pui-Chi Tin, Judy Wai Ping Yam, Maria Pik Wong, Zhi-Jie Xiao
      Cell Death & Disease.2020;[Epub]     CrossRef
    • INI-1 (SMARCB1)–Deficient Undifferentiated Sinonasal Carcinoma: Novel Paradigm of Molecular Testing in the Diagnosis and Management of Sinonasal Malignancies
      Khvaramze Shaverdashvili, Elham Azimi-Nekoo, Perry Cohen, Nadeem Akbar, Thomas J. Ow, Balazs Halmos, Enrico Castellucci
      The Oncologist.2020; 25(9): 738.     CrossRef
    • Genomic profiling in renal cell carcinoma
      Nazli Dizman, Errol J. Philip, Sumanta K. Pal
      Nature Reviews Nephrology.2020; 16(8): 435.     CrossRef
    • The Roles of the Histone Protein Modifier EZH2 in the Uterus and Placenta
      Ana M. Mesa, Cheryl S. Rosenfeld, Geetu Tuteja, Theresa I. Medrano, Paul S. Cooke
      Epigenomes.2020; 4(3): 20.     CrossRef
    • FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway
      Cheng-Cao Sun, Wei Zhu, Shu-Jun Li, Wei Hu, Jian Zhang, Yue Zhuo, Han Zhang, Juan Wang, Yu Zhang, Shao-Xin Huang, Qi-Qiang He, De-Jia Li
      Genome Medicine.2020;[Epub]     CrossRef
    • The long non‐coding RNA SNHG1 promotes bladder cancer progression by interacting with miR‐143‐3p and EZH2
      Wei Xiang, Lei Lyu, Tao Huang, Fuxin Zheng, Jingdong Yuan, Chuanhua Zhang, Guosong Jiang
      Journal of Cellular and Molecular Medicine.2020; 24(20): 11858.     CrossRef
    • Elevated expression of RUNX3 co-expressing with EZH2 in esophageal cancer patients from India
      Asad Ur Rehman, Mohammad Askandar Iqbal, Real Sumayya Abdul Sattar, Snigdha Saikia, Mohammad Kashif, Wasif Mohammad Ali, Subhash Medhi, Sundeep Singh Saluja, Syed Akhtar Husain
      Cancer Cell International.2020;[Epub]     CrossRef
    • MicroRNA-33b Suppresses Epithelial–Mesenchymal Transition Repressing the MYC–EZH2 Pathway in HER2+ Breast Carcinoma
      Birlipta Pattanayak, Iris Garrido-Cano, Anna Adam-Artigues, Eduardo Tormo, Begoña Pineda, Paula Cabello, Elisa Alonso, Begoña Bermejo, Cristina Hernando, María Teresa Martínez, Ana Rovira, Joan Albanell, Federico Rojo, Octavio Burgués, Juan Miguel Cejalvo
      Frontiers in Oncology.2020;[Epub]     CrossRef
    • Inhibition of EZH2 via the STAT3/HOTAIR signalling axis contributes to cell cycle arrest and apoptosis induced by polyphyllin I in human non-small cell lung cancer cells
      Hok Shing Li, Yao Xu
      Steroids.2020; 164: 108729.     CrossRef
    • EZH2 overexpression dampens tumor-suppressive signals via an EGR1 silencer to drive breast tumorigenesis
      Xiaowen Guan, Houliang Deng, Un Lam Choi, Zhengfeng Li, Yiqi Yang, Jianming Zeng, Yunze Liu, Xuanjun Zhang, Gang Li
      Oncogene.2020; 39(48): 7127.     CrossRef
    • RETRACTED: Exosome-Delivered LncHEIH Promotes Gastric Cancer Progression by Upregulating EZH2 and Stimulating Methylation of the GSDME Promoter
      Yan Lu, Kaiqing Hou, Mengsen Li, Xiaobin Wu, Shaochun Yuan
      Frontiers in Cell and Developmental Biology.2020;[Epub]     CrossRef
    • Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness
      Ralf Hass, Juliane von der Ohe, Hendrik Ungefroren
      Cancers.2020; 12(12): 3716.     CrossRef
    • The EZH2–PHACTR2–AS1–Ribosome Axis induces Genomic Instability and Promotes Growth and Metastasis in Breast Cancer
      Wenhui Chu, Xi Zhang, Lihua Qi, Yenan Fu, Peng Wang, Wei Zhao, Juan Du, Jing Zhang, Jun Zhan, Yunling Wang, Wei-Guo Zhu, Yu Yu, Hongquan Zhang
      Cancer Research.2020; 80(13): 2737.     CrossRef
    • Inhibition of EZH2 Enhances the Antitumor Efficacy of Metformin in Prostate Cancer
      Yifan Kong, Yanquan Zhang, Fengyi Mao, Zhuangzhuang Zhang, Zhiguo Li, Ruixin Wang, Jinghui Liu, Xiaoqi Liu
      Molecular Cancer Therapeutics.2020; 19(12): 2490.     CrossRef
    • Aberrant differential expression of EZH2 and H3K27me3 in extranodal NK/T-cell lymphoma, nasal type, is associated with disease progression and prognosis
      Jumei Liu, Li Liang, Sixia Huang, Lin Nong, Dong Li, Bo Zhang, Ting Li
      Human Pathology.2019; 83: 166.     CrossRef
    • Retracted: Long noncoding RNA TALNEC2 plays an oncogenic role in breast cancer by binding to EZH2 to target p57KIP2 and involving in p‐p38 MAPK and NF‐κB pathways
      Enqi Qiao, Daobao Chen, Qinglin Li, Weiliang Feng, Xingfei Yu, Xiping Zhang, Liang Xia, Ju Jin, Hongjian Yang
      Journal of Cellular Biochemistry.2019; 120(3): 3978.     CrossRef
    • Interaction of EZH2 and P65 is involved in the arsenic trioxide-induced anti-angiogenesis in human triple-negative breast cancer cells
      Fei Jiang, Yuan Li, Lu Si, Zengli Zhang, Zhong Li
      Cell Biology and Toxicology.2019; 35(4): 361.     CrossRef
    • lncRNA SNHG6 regulates EZH2 expression by sponging miR-26a/b and miR-214 in colorectal cancer
      Mu Xu, Xiaoxiang Chen, Kang Lin, Kaixuan Zeng, Xiangxiang Liu, Xueni Xu, Bei Pan, Tao Xu, Li Sun, Bangshun He, Yuqin Pan, Huiling Sun, Shukui Wang
      Journal of Hematology & Oncology.2019;[Epub]     CrossRef
    • Genome-wide expression analysis reveals six contravened targets of EZH2 associated with breast cancer patient survival
      Kanchan Kumari, Biswajit Das, Amit K. Adhya, Arabinda K. Rath, Sandip K. Mishra
      Scientific Reports.2019;[Epub]     CrossRef
    • LncRNA ADAMTS9-AS2 promotes tongue squamous cell carcinoma proliferation, migration and EMT via the miR-600/EZH2 axis
      Yingru Li, Quan Wan, Weiwei Wang, Lianxi Mai, Liujuan Sha, Mubarak Mashrah, Zhaoyu Lin, Chaobin Pan
      Biomedicine & Pharmacotherapy.2019; 112: 108719.     CrossRef
    • New directions in treating peripheral T-cell lymphomas (PTCL): leveraging epigenetic modifiers alone and in combination
      Helen Ma, Owen A. O’Connor, Enrica Marchi
      Expert Review of Hematology.2019; 12(3): 137.     CrossRef
    • iPS-Cell Technology and the Problem of Genetic Instability—Can It Ever Be Safe for Clinical Use?
      Stephen W. Attwood, Michael J. Edel
      Journal of Clinical Medicine.2019; 8(3): 288.     CrossRef
    • Protein dynamics analysis reveals that missense mutations in cancer‐related genes appear frequently on hinge‐neighboring residues
      Jan Fehmi Sayılgan, Türkan Haliloğlu, Mehmet Gönen
      Proteins: Structure, Function, and Bioinformatics.2019; 87(6): 512.     CrossRef
    • Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit Is Required for Uterine Epithelial Integrity
      Xin Fang, Nan Ni, John P. Lydon, Ivan Ivanov, Kayla J. Bayless, Monique Rijnkels, Qinglei Li
      The American Journal of Pathology.2019; 189(6): 1212.     CrossRef
    • Prolactin Receptor Signaling Regulates a Pregnancy-Specific Transcriptional Program in Mouse Islets
      Mark E Pepin, Hayden H Bickerton, Maigen Bethea, Chad S Hunter, Adam R Wende, Ronadip R Banerjee
      Endocrinology.2019; 160(5): 1150.     CrossRef
    • Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation
      Jie Zhou, Shuo Huang, Zhongyu Wang, Jiani Huang, Liang Xu, Xuefeng Tang, Yisong Y. Wan, Qi-jing Li, Alistair L. J. Symonds, Haixia Long, Bo Zhu
      Nature Communications.2019;[Epub]     CrossRef
    • Silencing of microRNA-708 promotes cell growth and epithelial-to-mesenchymal transition by activating the SPHK2/AKT/β-catenin pathway in glioma
      Yan Chen, Xubin Deng, Weiquan Chen, Pengwei Shi, Mei Lian, Hongxiao Wang, Kewan Wang, Dadi Qian, Dong Xiao, Hao Long
      Cell Death & Disease.2019;[Epub]     CrossRef
    • EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive chronic lymphocytic leukaemia
      Subazini Thankaswamy Kosalai, Mohammad Hamdy Abdelrazak Morsy, Nikos Papakonstantinou, Larry Mansouri, Niki Stavroyianni, Chandrasekhar Kanduri, Kostas Stamatopoulos, Richard Rosenquist, Meena Kanduri
      Epigenetics.2019; 14(11): 1125.     CrossRef
    • Current state of melanoma diagnosis and treatment
      Lauren E. Davis, Sara C. Shalin, Alan J. Tackett
      Cancer Biology & Therapy.2019; 20(11): 1366.     CrossRef
    • DZNep-mediated apoptosis in B-cell lymphoma is independent of the lymphoma type, EZH2 mutation status and MYC, BCL2 or BCL6 translocations
      Chidimma Agatha Akpa, Karsten Kleo, Dido Lenze, Elisabeth Oker, Lora Dimitrova, Michael Hummel, Francesco Bertolini
      PLOS ONE.2019; 14(8): e0220681.     CrossRef
    • HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia
      Zhengchang He, Siyu Zhang, Dan Ma, Qin Fang, Liping Yang, Shaoxian Shen, Ying Chen, Lingli Ren, Jishi Wang
      Journal of Translational Medicine.2019;[Epub]     CrossRef
    • Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators
      Khaled Alsayegh, Lorena V. Cortés-Medina, Gerardo Ramos-Mandujano, Heba Badraiq, Mo Li
      Current Genomics.2019; 20(6): 438.     CrossRef
    • Long non‐coding small nucleolar RNA host genes in digestive cancers
      Huan Yang, Zheng Jiang, Shuang Wang, Yongbing Zhao, Xiaomei Song, Yufeng Xiao, Shiming Yang
      Cancer Medicine.2019; 8(18): 7693.     CrossRef
    • Aberrant Expression of EZH2 in Pediatric Patients with Myelodysplastic Syndrome: A Potential Biomarker of Leukemic Evolution
      Teresa de Souza Fernandez, Tatiana Fonseca Alvarenga, Elaiza Almeida Antônio de Kós, Viviane Lamim Lovatel, Rita de Cássia Tavares, Elaine Sobral da Costa, Cecília de Souza Fernandez, Eliana Abdelhay
      BioMed Research International.2019; 2019: 1.     CrossRef
    • Epigenetics of Bladder Cancer: Where Biomarkers and Therapeutic Targets Meet
      Victor G. Martinez, Ester Munera-Maravilla, Alejandra Bernardini, Carolina Rubio, Cristian Suarez-Cabrera, Cristina Segovia, Iris Lodewijk, Marta Dueñas, Mónica Martínez-Fernández, Jesus Maria Paramio
      Frontiers in Genetics.2019;[Epub]     CrossRef
    • Cigarette smoke affects the onco-suppressor DAB2IP expression in bronchial epithelial cells of COPD patients
      Giulia Anzalone, Giuseppe Arcoleo, Fabio Bucchieri, Angela M. Montalbano, Roberto Marchese, Giusy D. Albano, Caterina Di Sano, Monica Moscato, Rosalia Gagliardo, Fabio L. M. Ricciardolo, Mirella Profita
      Scientific Reports.2019;[Epub]     CrossRef
    • Stratifying nonfunctional pituitary adenomas into two groups distinguished by macrophage subtypes
      Garima Yagnik, Martin J. Rutowski, Sumedh S. Shah, Manish K. Aghi
      Oncotarget.2019; 10(22): 2212.     CrossRef
    • Genome‑wide analysis reveals the emerging roles of long non‑coding RNAs in cancer (Review)
      Xiaoxia Ren
      Oncology Letters.2019;[Epub]     CrossRef
    • EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer
      H Yamaguchi, Y Du, K Nakai, M Ding, S-S Chang, J L Hsu, J Yao, Y Wei, L Nie, S Jiao, W-C Chang, C-H Chen, Y Yu, G N Hortobagyi, M-C Hung
      Oncogene.2018; 37(2): 208.     CrossRef
    • Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-d
      Pei-Pei Kung, Patrick Bingham, Alexei Brooun, Michael Collins, Ya-Li Deng, Dac Dinh, Connie Fan, Ketan S. Gajiwala, Rita Grantner, Hovhannes J. Gukasyan, Wenyue Hu, Buwen Huang, Robert Kania, Susan E. Kephart, Cody Krivacic, Robert A. Kumpf, Penney Khamph
      Journal of Medicinal Chemistry.2018; 61(3): 650.     CrossRef
    • Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA
      Kanchan Kumari, Biswajit Das, Amit Adhya, Sanjib Chaudhary, Shantibhusan Senapati, Sandip K. Mishra
      Cell Death & Disease.2018;[Epub]     CrossRef
    • Long noncoding RNA GAS5 promotes bladder cancer cells apoptosis through inhibiting EZH2 transcription
      Miao Wang, Chen Guo, Liang Wang, Gang Luo, Chao Huang, Yawei Li, Dong Liu, Fuqing Zeng, Guosong Jiang, Xingyuan Xiao
      Cell Death & Disease.2018;[Epub]     CrossRef
    • Valproic Acid Promotes Apoptosis and Cisplatin Sensitivity Through Downregulation of H19 Noncoding RNA in Ovarian A2780 Cells
      Zahre Sajadpoor, Zeinab Amini-Farsani, Hossein Teimori, Mehdi Shamsara, Mohammad Hossein Sangtarash, Payam Ghasemi-Dehkordi, Farrokh Yadollahi
      Applied Biochemistry and Biotechnology.2018; 185(4): 1132.     CrossRef
    • Epigenetic dysregulation of key developmental genes in radiation‐induced rat mammary carcinomas
      Kazuhiro Daino, Mayumi Nishimura, Tatsuhiko Imaoka, Masaru Takabatake, Takamitsu Morioka, Yukiko Nishimura, Yoshiya Shimada, Shizuko Kakinuma
      International Journal of Cancer.2018; 143(2): 343.     CrossRef
    • The role of enhancer of zeste homolog 2: From viral epigenetics to the carcinogenesis of hepatocellular carcinoma
      Luca Sanna, Irene Marchesi, Mariarosa A. B. Melone, Luigi Bagella
      Journal of Cellular Physiology.2018; 233(9): 6508.     CrossRef
    • Decreased expression of microRNA-26b in locally advanced and inflammatory breast cancer
      Qingqing Ding, Yan Wang, Zhuang Zuo, Yun Gong, Savitri Krishnamurthy, Chia-Wei Li, Yun-Ju Lai, Wei Wei, Jing Wang, Ganiraju C. Manyam, Lixia Diao, Xinna Zhang, Feng Lin, William F. Symmans, Li Sun, Chang-Gong Liu, Xiuping Liu, Bisrat G. Debeb, Naoto T. Ue
      Human Pathology.2018; 77: 121.     CrossRef
    • EZH2 induces the expression of miR-1301 as a negative feedback control mechanism in triple negative breast cancer
      Qiuju Wu, Zekun Chen, Guihua Zhang, Wenhui Zhou, You Peng, Rong Liu, Ceshi Chen, Jing Feng
      Acta Biochimica et Biophysica Sinica.2018; 50(7): 693.     CrossRef
    • Impact of OGT deregulation on EZH2 target genes FOXA1 and FOXC1 expression in breast cancer cells
      Ewa Forma, Paweł Jóźwiak, Piotr Ciesielski, Agnieszka Zaczek, Katarzyna Starska, Magdalena Bryś, Anna Krześlak, Gokul M. Das
      PLOS ONE.2018; 13(6): e0198351.     CrossRef
    • Anti-tumor and anti-metastasis activities of honey bee larvae powder by suppressing the expression of EZH2
      Masakatsu Kageyama, Kejuan Li, Shuang Sun, Guoqing Xing, Ran Gao, Zhongfang Lei, Zhenya Zhang
      Biomedicine & Pharmacotherapy.2018; 105: 690.     CrossRef
    • Epigenetic silencing of tumor suppressor gene CDKN1A by oncogenic long non-coding RNA SNHG1 in cholangiocarcinoma
      Yang Yu, Mingjiong Zhang, Ni Wang, Quanpeng Li, Jian Yang, Shuai Yan, Xuezhi He, Guozhong Ji, Lin Miao
      Cell Death & Disease.2018;[Epub]     CrossRef
    • Emerging roles of Myc in stem cell biology and novel tumor therapies
      Go J. Yoshida
      Journal of Experimental & Clinical Cancer Research.2018;[Epub]     CrossRef
    • The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p
      Mu Xu, Xiaoxiang Chen, Kang Lin, Kaixuan Zeng, Xiangxiang Liu, Bei Pan, Xueni Xu, Tao Xu, Xiuxiu Hu, Li Sun, Bangshun He, Yuqin Pan, Huiling Sun, Shukui Wang
      Molecular Cancer.2018;[Epub]     CrossRef
    • Long noncoding RNA PCAT6 functions as an oncogene by binding to EZH2 and suppressing LATS2 in non-small-cell lung cancer
      Xuefei Shi, Zhili Liu, Zhicong Liu, Xueren Feng, Feng Hua, Xixian Hu, Bin Wang, Kaihua Lu, Fengqi Nie
      EBioMedicine.2018; 37: 177.     CrossRef
    • DUXAP8, a pseudogene derived lncRNA, promotes growth of pancreatic carcinoma cells by epigenetically silencing CDKN1A and KLF2
      Yifan Lian, Jiebin Yang, Yikai Lian, Chuangxing Xiao, Xuezhen Hu, Hongzhi Xu
      Cancer Communications.2018; 38(1): 1.     CrossRef
    • EZH2, HIF-1, and Their Inhibitors: An Overview on Pediatric Cancers
      Marco Papale, Elisabetta Ferretti, Giuseppe Battaglia, Diana Bellavia, Antonello Mai, Marco Tafani
      Frontiers in Pediatrics.2018;[Epub]     CrossRef
    • Long Noncoding RNA ANRIL Supports Proliferation of Adult T-Cell Leukemia Cells through Cooperation with EZH2
      Zaowen Song, Wencai Wu, Mengyun Chen, Wenzhao Cheng, Juntao Yu, Jinyong Fang, Lingling Xu, Jun-ichirou Yasunaga, Masao Matsuoka, Tiejun Zhao, Viviana Simon
      Journal of Virology.2018;[Epub]     CrossRef
    • MET/ERK and MET/JNK Pathway Activation Is Involved in BCR-ABL Inhibitor-resistance in Chronic Myeloid Leukemia
      Masanobu Tsubaki
      YAKUGAKU ZASSHI.2018; 138(12): 1461.     CrossRef
    • EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes
      Taylor Harding, Jessica Swanson, Brian Van Ness
      Oncotarget.2018; 9(31): 21930.     CrossRef
    • The untold stories of the speech gene, the FOXP2 cancer gene
      Maria Jesus Herrero, Yorick Gitton
      Genes & Cancer.2018; 9(1-2): 11.     CrossRef
    • SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer
      W Lu, S Liu, B Li, Y Xie, M G Izban, B R Ballard, S A Sathyanarayana, S E Adunyah, R J Matusik, Z Chen
      Oncogene.2017; 36(10): 1364.     CrossRef
    • Circ100284, via miR-217 regulation of EZH2, is involved in the arsenite-accelerated cell cycle of human keratinocytes in carcinogenesis
      Junchao Xue, Yang Liu, Fei Luo, Xiaolin Lu, Hui Xu, Xinlu Liu, Lu Lu, Qianlei Yang, Chao Chen, Weimin Fan, Qizhan Liu
      Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2017; 1863(3): 753.     CrossRef
    • Regulation of cancer epigenomes with a histone-binding synthetic transcription factor
      David B. Nyer, Rene M. Daer, Daniel Vargas, Caroline Hom, Karmella A. Haynes
      npj Genomic Medicine.2017;[Epub]     CrossRef
    • Metastatic biomarkers in synovial sarcoma
      Rosalia de Necochea-Campion, Lee M. Zuckerman, Hamid R. Mirshahidi, Shahrzad Khosrowpour, Chien-Shing Chen, Saied Mirshahidi
      Biomarker Research.2017;[Epub]     CrossRef
    • Interplay of DNA methyltransferase 1 and EZH2 through inactivation of Stat3 contributes to β-elemene-inhibited growth of nasopharyngeal carcinoma cells
      JingJing Wu, Qing Tang, LiJuan Yang, YuQing Chen, Fang Zheng, Swei Sunny Hann
      Scientific Reports.2017;[Epub]     CrossRef
    • Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3
      Maureen M. Sherry-Lynes, Sejuti Sengupta, Shreya Kulkarni, Brent H. Cochran, Anita B. Hjelmeland
      PLOS ONE.2017; 12(4): e0174775.     CrossRef
    • Modulation of HAT activity by the BRCA2 N372H variation is a novel mechanism of paclitaxel resistance in breast cancer cell lines
      Woo Sun Kwon, Sun Young Rha, Hei-Cheul Jeung, Tae Soo Kim, Hyun Cheol Chung
      Biochemical Pharmacology.2017; 138: 163.     CrossRef
    • Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors
      Azadeh Amirnasr, Rob M. Verdijk, Patricia F. van Kuijk, Walter Taal, Stefan Sleijfer, Erik A. C. Wiemer, Marta M. Alonso
      PLOS ONE.2017; 12(8): e0183155.     CrossRef
    • Morphoproteomics, E6/E7 in-situ hybridization, and biomedical analytics define the etiopathogenesis of HPV-associated oropharyngeal carcinoma and provide targeted therapeutic options
      Robert E. Brown, Syed Naqvi, Mary F. McGuire, Jamie Buryanek, Ron J. Karni
      Journal of Otolaryngology - Head & Neck Surgery.2017;[Epub]     CrossRef
    • Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation
      Hyunjoo Kwon, Kyoungsub Song, Chang Han, Jinqiang Zhang, Lu Lu, Weina Chen, Tong Wu
      The American Journal of Pathology.2017; 187(10): 2288.     CrossRef
    • The role of EZH2 in overall survival of colorectal cancer: a meta-analysis
      Laura Vilorio-Marqués, Vicente Martín, Cristina Diez-Tascón, María Francisca González-Sevilla, Tania Fernández-Villa, Emiliano Honrado, Veronica Davila-Batista, Antonio J. Molina
      Scientific Reports.2017;[Epub]     CrossRef
    • Identification of coexistence of BRAF V600E mutation and EZH2 gain specifically in melanoma as a promising target for combination therapy
      Huan Yu, Meng Ma, Junya Yan, Longwen Xu, Jiayi Yu, Jie Dai, Tianxiao Xu, Huan Tang, Xiaowen Wu, Siming Li, Bin Lian, Lili Mao, Zhihong Chi, Chuanliang Cui, Jun Guo, Yan Kong
      Journal of Translational Medicine.2017;[Epub]     CrossRef
    • Decreased expression of JMJD3 predicts poor prognosis of patients with clear cell renal cell carcinoma
      Jiajun Wang, Li Liu, Qilai Long, Qi Bai, Yu Xia, Wei Xi, Jiejie Xu, Jianming Guo
      Oncology Letters.2017; 14(2): 1550.     CrossRef
    • Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells
      Masanobu Tsubaki, Tomoya Takeda, Toshiki Kino, Kazuko Sakai, Tatsuki Itoh, Motohiro Imano, Takashi Nakayama, Kazuto Nishio, Takao Satou, Shozo Nishida
      Oncotarget.2017; 8(24): 38717.     CrossRef
    • Methylation-mediated silencing of microRNA-211 promotes cell growth and epithelial to mesenchymal transition through activation of the AKT/β-catenin pathway in GBM
      Weidong Li, Xiaobo Miao, Lingling Liu, Yue Zhang, Xuejun Jin, Xiaojun Luo, Hai Gao, Xubin Deng
      Oncotarget.2017; 8(15): 25167.     CrossRef
    • EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis
      Kei Ihira, Peixin Dong, Ying Xiong, Hidemichi Watari, Yosuke Konno, Sharon JB Hanley, Masayuki Noguchi, Noriyuki Hirata, Futoshi Suizu, Takahiro Yamada, Masataka Kudo, Noriaki Sakuragi
      Oncotarget.2017; 8(8): 13509.     CrossRef
    • Inhibition of enhancer of zeste homolog 2 increases the expression of p16 and suppresses the proliferation and migration of ovarian carcinoma cells in�vitro and in�vivo
      Fangfang Lu, Hong Xu, Qi Wang, Meiyi Li, Jiahua Meng, Yan Kuang
      Oncology Letters.2017;[Epub]     CrossRef
    • miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer
      Hardik R. Mody, Sau Wai Hung, Rakesh K. Pathak, Jazmine Griffin, Zobeida Cruz-Monserrate, Rajgopal Govindarajan
      Molecular Cancer Research.2017; 15(8): 1029.     CrossRef
    • TET-Mediated Sequestration of miR-26 Drives EZH2 Expression and Gastric Carcinogenesis
      Min Deng, Ruixin Zhang, Zhengxi He, Qinwei Qiu, Xihong Lu, Jiang Yin, Hao Liu, Xiaoting Jia, Zhimin He
      Cancer Research.2017; 77(22): 6069.     CrossRef
    • The role of the polycomb repressive complex pathway in T and NK cell lymphoma: biological and prognostic implications
      Soo Hee Kim, Woo Ick Yang, Yoo Hong Min, Young Hyeh Ko, Sun Och Yoon
      Tumor Biology.2016; 37(2): 2037.     CrossRef
    • Interference with endogenous EZH2 reverses the chemotherapy drug resistance in cervical cancer cells partly by up-regulating Dicer expression
      Liqiong Cai, Zehua Wang, Denghua Liu
      Tumor Biology.2016; 37(5): 6359.     CrossRef
    • The Ezh2 polycomb group protein drives an aggressive phenotype in melanoma cancer stem cells and is a target of diet derived sulforaphane
      Matthew L. Fisher, Gautam Adhikary, Dan Grun, David M. Kaetzel, Richard L. Eckert
      Molecular Carcinogenesis.2016; 55(12): 2024.     CrossRef
    • Problems of glioblastoma multiforme drug resistance
      A. A. Stavrovskaya, S. S. Shushanov, E. Yu. Rybalkina
      Biochemistry (Moscow).2016; 81(2): 91.     CrossRef
    • High EZH2 Protein Expression Is Associated with Poor Overall Survival in Patients with Luminal A Breast Cancer
      Si-Hyong Jang, Jong Eun Lee, Mee-Hye Oh, Ji-Hye Lee, Hyun Deuk Cho, Kyung-Ju Kim, Sung Yong Kim, Sun Wook Han, Han Jo Kim, Sang Byung Bae, Hyun Ju Lee
      Journal of Breast Cancer.2016; 19(1): 53.     CrossRef
    • Expression of Mirna-26B in the Diagnosis and Prognosis of Patients with Non-Small-Cell Lung Cancer
      Li-Peng Jiang, Zhi-Tu Zhu, Chun-Yan He
      Future Oncology.2016; 12(9): 1105.     CrossRef
    • Targeting NK Cells for Anticancer Immunotherapy: Clinical and Preclinical Approaches
      Sebastian Carotta
      Frontiers in Immunology.2016;[Epub]     CrossRef
    • Role of EZH2 histone methyltrasferase in melanoma progression and metastasis
      Fade Mahmoud, Bradley Shields, Issam Makhoul, Laura F. Hutchins, Sara C. Shalin, Alan J. Tackett
      Cancer Biology & Therapy.2016; 17(6): 579.     CrossRef
    • Prognostic value of UTX expression in patients with clear cell renal cell carcinoma
      Jiajun Wang, Li Liu, Wei Xi, Qilai Long, Yiwei Wang, Qi Bai, Yu Xia, Jiejie Xu, Jianming Guo
      Urologic Oncology: Seminars and Original Investigations.2016; 34(8): 338.e19.     CrossRef
    • Squamous Cell Cancers: A Unified Perspective on Biology and Genetics
      G. Paolo Dotto, Anil K. Rustgi
      Cancer Cell.2016; 29(5): 622.     CrossRef
    • Genomic and Epigenomic Alterations in Cancer
      Balabhadrapatruni V.S.K. Chakravarthi, Saroj Nepal, Sooryanarayana Varambally
      The American Journal of Pathology.2016; 186(7): 1724.     CrossRef
    • Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma
      Yusuke Furukawa, Jiro Kikuchi
      International Journal of Hematology.2016; 104(3): 281.     CrossRef
    • Down-Regulation of TSLP After EZH2 Silencing in ESCC Cell Line
      Gholamreza Karami Madani, Abolfazl Rad, Mohammad Mahdi Forghanifard
      Journal of Biomedicine.2016;[Epub]     CrossRef
    • High EZH2 expression is correlated to metastatic disease in pediatric soft tissue sarcomas
      Maria Ramaglia, Velia D’Angelo, Adriana Iannotta, Daniela Di Pinto, Elvira Pota, Maria Carmen Affinita, Vittoria Donofrio, Maria Elena Errico, Angela Lombardi, Cristiana Indolfi, Fiorina Casale, Michele Caraglia
      Cancer Cell International.2016;[Epub]     CrossRef
    • DNA-PK-mediated phosphorylation of EZH2 regulates the DNA damage-induced apoptosis to maintain T-cell genomic integrity
      Y Wang, H Sun, J Wang, H Wang, L Meng, C Xu, M Jin, B Wang, Y Zhang, Y Zhang, T Zhu
      Cell Death & Disease.2016; 7(7): e2316.     CrossRef
    • Significance of EZH2 expression in canine mammary tumors
      Hyun-Ji Choi, Sungwoong Jang, Jae-Eun Ryu, Hyo-Ju Lee, Han-Byul Lee, Woo-Sung Ahn, Hye-Jin Kim, Hyo-Jin Lee, Hee Jin Lee, Gyung-Yub Gong, Woo-Chan Son
      BMC Veterinary Research.2016;[Epub]     CrossRef
    • Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitabl
      Rishi G. Vaswani, Victor S. Gehling, Les A. Dakin, Andrew S. Cook, Christopher G. Nasveschuk, Martin Duplessis, Priyadarshini Iyer, Srividya Balasubramanian, Feng Zhao, Andrew C. Good, Robert Campbell, Christina Lee, Nico Cantone, Richard T. Cummings, Emm
      Journal of Medicinal Chemistry.2016; 59(21): 9928.     CrossRef
    • MiR-101 Targets the EZH2/Wnt/β-Catenin the Pathway to Promote the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells
      Hongrui Wang, Yake Meng, Quanjun Cui, Fujun Qin, Haisong Yang, Yu Chen, Yajun Cheng, Jiangang Shi, Yongfei Guo
      Scientific Reports.2016;[Epub]     CrossRef
    • EZH2 mediates lidamycin-induced cellular senescence through regulating p21 expression in human colon cancer cells
      Ming-Quan Sha, Xiao-Li Zhao, Liang Li, Li-Hui Li, Yi Li, Tian-Geng Dong, Wei-Xin Niu, Li-Jun Jia, Rong-Guang Shao, Yong-Su Zhen, Zhen Wang
      Cell Death & Disease.2016; 7(11): e2486.     CrossRef
    • Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: a case report
      Joseph Hatem, April M. Schrank-Hacker, Christopher D. Watt, Jennifer J. D. Morrissette, Adam I. Rubin, Ellen J. Kim, Sunita D. Nasta, Mariusz A. Wasik, Agata M. Bogusz
      Diagnostic Pathology.2016;[Epub]     CrossRef
    • Expression Profile and Function Analysis of LncRNAs during Priming Phase of Rat Liver Regeneration
      Jun Li, Wei Jin, Yanli Qin, Weiming Zhao, Cuifang Chang, Cunshuan Xu, Klaus Roemer
      PLOS ONE.2016; 11(6): e0156128.     CrossRef
    • Non-Canonical EZH2 Transcriptionally Activates RelB in Triple Negative Breast Cancer
      Cortney L. Lawrence, Albert S. Baldwin, Aamir Ahmad
      PLOS ONE.2016; 11(10): e0165005.     CrossRef
    • Identification of Polycomb Group Protein EZH2-Mediated DNA Mismatch Repair Gene MSH2 in Human Uterine Fibroids
      Qiwei Yang, Archana Laknaur, Lelyand Elam, Nahed Ismail, Larisa Gavrilova-Jordan, John Lue, Michael P. Diamond, Ayman Al-Hendy
      Reproductive Sciences.2016; 23(10): 1314.     CrossRef
    • The relationship between EZH2 expression and microRNA-31 in colorectal cancer and the role in evolution of the serrated pathway
      Hiroyoshi Kurihara, Reo Maruyama, Kazuya Ishiguro, Shinichi Kanno, Itaru Yamamoto, Keisuke Ishigami, Kei Mitsuhashi, Hisayoshi Igarashi, Miki Ito, Tokuma Tanuma, Yasutaka Sukawa, Kenji Okita, Tadashi Hasegawa, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shin
      Oncotarget.2016; 7(11): 12704.     CrossRef
    • The histone methyltransferase EZH2 as a novel prosurvival factor in clinically aggressive chronic lymphocytic leukemia
      Nikos Papakonstantinou, Stavroula Ntoufa, Elisavet Chartomatsidou, Konstantia Kotta, Andreas Agathangelidis, Lefki Giassafaki, Tzeni Karamanli, Panagiota Bele, Theodoros Moysiadis, Panagiotis Baliakas, Lesley Ann Sutton, Niki Stavroyianni, Achilles Anagno
      Oncotarget.2016; 7(24): 35946.     CrossRef
    • Proximal and distal regulation of the HYAL1 gene cluster by the estrogen receptor α in breast cancer cells
      Lydia Edjekouane, Samira Benhadjeba, Maïka Jangal, Hubert Fleury, Nicolas Gévry, Euridice Carmona, André Tremblay
      Oncotarget.2016; 7(47): 77276.     CrossRef
    • Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential
      Ranran Sun, Jacson Shen, Yan Gao, Yubing Zhou, Zujiang Yu, Francis Hornicek, Quancheng Kan, Zhenfeng Duan
      Oncotarget.2016; 7(25): 38333.     CrossRef
    • GSK3β inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers
      How-Wen Ko, Heng-Huan Lee, Longfei Huo, Weiya Xia, Cheng-Chieh Yang, Jennifer L. Hsu, Long-Yuan Li, Chien-Chen Lai, Li-Chuan Chan, Chien-Chia Cheng, Adam M. Labaff, Hsin-Wei Liao, Seung-Oe Lim, Chia-Wei Li, Yongkun Wei, Lei Nie, Hirohito Yamaguchi, Mien-C
      Oncotarget.2016; 7(35): 57131.     CrossRef
    • Upregulation of the long noncoding RNA TUG1 promotes proliferation and migration of esophageal squamous cell carcinoma
      Youtao Xu, Jie Wang, Mantang Qiu, Lei Xu, Ming Li, Feng Jiang, Rong Yin, Lin Xu
      Tumor Biology.2015; 36(3): 1643.     CrossRef
    • Role of the ubiquitin proteasome system in hematologic malignancies
      Anagh A. Sahasrabuddhe, Kojo S. J. Elenitoba‐Johnson
      Immunological Reviews.2015; 263(1): 224.     CrossRef
    • The roles of chromatin-remodelers and epigenetic modifiers in kidney cancer
      Lili Liao, Joseph R. Testa, Haifeng Yang
      Cancer Genetics.2015; 208(5): 206.     CrossRef
    • The role of aberrant proteolysis in lymphomagenesis
      Anagh A. Sahasrabuddhe, Kojo S.J. Elenitoba-Johnson
      Current Opinion in Hematology.2015; 22(4): 369.     CrossRef
    • Small Molecule Inhibitors of EZH2: the Emerging Translational Landscape
      Heike Keilhack, Jesse J Smith
      Epigenomics.2015; 7(3): 337.     CrossRef
    • Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma
      Yang-Fan Lv, Guang-Ning Yan, Gang Meng, Xi Zhang, Qiao-Nan Guo
      Scientific Reports.2015;[Epub]     CrossRef
    • Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma
      Mehnaz Khan, Laura L Walters, Qiang Li, Dafydd G Thomas, Jason M L Miller, Qitao Zhang, Andrew P Sciallis, Yu Liu, Brian J Dlouhy, Patrice E Fort, Steven M Archer, Hakan Demirci, Yali Dou, Rajesh C Rao
      Laboratory Investigation.2015; 95(11): 1278.     CrossRef
    • Methyltransferase expression and tumor suppressor gene methylation in sporadic and familial colorectal cancer
      Emmi I. Joensuu, Taina T. Nieminen, Johanna E. Lotsari, Walter Pavicic, Wael M. Abdel‐Rahman, Päivi Peltomäki
      Genes, Chromosomes and Cancer.2015; 54(12): 776.     CrossRef
    • Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma
      Jiro Kikuchi, Daisuke Koyama, Taeko Wada, Tohru Izumi, Peter O. Hofgaard, Bjarne Bogen, Yusuke Furukawa
      Journal of Clinical Investigation.2015; 125(12): 4375.     CrossRef
    • Overexpression of enhancer of zeste homolog 2 (EZH2) characterizes an aggressive subset of prostate cancers and predicts patient prognosis independently from pre- and postoperatively assessed clinicopathological parameters
      Nathaniel Melling, Erik Thomsen, Maria Christina Tsourlakis, Martina Kluth, Claudia Hube-Magg, Sarah Minner, Christina Koop, Markus Graefen, Hans Heinzer, Corinna Wittmer, Guido Sauter, Waldemar Wilczak, Hartwig Huland, Ronald Simon, Thorsten Schlomm, Ste
      Carcinogenesis.2015; 36(11): 1333.     CrossRef
    • EZH2 in Bladder Cancer, a Promising Therapeutic Target
      Mónica Martínez-Fernández, Carolina Rubio, Cristina Segovia, Fernando López-Calderón, Marta Dueñas, Jesús Paramio
      International Journal of Molecular Sciences.2015; 16(11): 27107.     CrossRef
    • siRNA Silencing EZH2 Reverses Cisplatin-resistance of Human Non-small Cell Lung and Gastric Cancer Cells
      Wen Zhou, Jian Wang, Wang-Ying Man, Qing-Wei Zhang, Wen-Gui Xu
      Asian Pacific Journal of Cancer Prevention.2015; 16(6): 2425.     CrossRef
    • H3K27me3 is an Epigenetic Mark of Relevance in Endometriosis
      Mariano Colón-Caraballo, Janice B. Monteiro, Idhaliz Flores
      Reproductive Sciences.2015; 22(9): 1134.     CrossRef
    • A Gene Regulatory Program in Human Breast Cancer
      Renhua Li, John Campos, Joji Iida
      Genetics.2015; 201(4): 1341.     CrossRef
    • MiR-101 reverses the hypomethylation of the LMO3 promoter in glioma cells
      Xiaoping Liu, Qianqian Lei, Zhibin Yu, Gang Xu, Hailin Tang, Wei Wang, Zeyou Wang, Guiyuan Li, Minghua Wu
      Oncotarget.2015; 6(10): 7930.     CrossRef
    • Enhancer of zeste acts as a major developmental regulator ofCiona intestinalisembryogenesis
      Emilie Le Goff, Camille Martinand-Mari, Marianne Martin, Jérôme Feuillard, Yvan Boublik, Nelly Godefroy, Paul Mangeat, Stephen Baghdiguian, Giacomo Cavalli
      Biology Open.2015; 4(9): 1109.     CrossRef

    • PubReader PubReader
    • ePub LinkePub Link
    • Cite
      CITE
      export Copy Download
      Close
      Download Citation
      Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.
      Format:
      • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
      • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
      Include:
      • Citation for the content below
      Regulation and Role of EZH2 in Cancer
      Cancer Res Treat. 2014;46(3):209-222.   Published online July 15, 2014
      DOI: https://doi.org/10.4143/crt.2014.46.3.209
      Close
    • XML DownloadXML Download
    Figure
    • 0
    • 1
    • 2
    Regulation and Role of EZH2 in Cancer
    Image Image Image
    Fig. 1. Regulators of EZH2 expression and DNA targeting in cancer. EZH2 expression is regulated by various oncogenic transcription factors and tumor suppressor miRNAs. Access to the specific DNA sites is regulated by various transcription factors and noncoding RNAs (ncRNAs).
    Fig. 2. Post-translational modifications of EZH2. EZH2 is phosphorylated at S21, T345, T372, T416, T487, Y641, and S734 by the indicated kinases. S75 is glycosylated by O-linked N-acetylglucosamine transferase (OGT). In addition, EZH2 is ubiquitinated by Smurf2, β-TrCP, and PRAJA1 and undergoes degradation.
    Fig. 3. Various functions of EZH2 in human cancer. EZH2 silences multiple tumor suppressors such as INK4A/ARF and E-cadherin via canonical H3K27me3. EZH2 also methylates substrates other than H3K27, such as STAT3 and RORα. Furthermore, EZH2 has a methylase-independent function.

    Fig. 1.

    Fig. 2.

    Fig. 3.

    Regulation and Role of EZH2 in Cancer
    Cancer Res Treat : Cancer Research and Treatment
    © Korean Cancer Association.
    Close layer
    TOP