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The Histone Deacetylase Inhibitor Entinostat Mediates HER2 Downregulation in Gastric Cancer, Providing the Basis for Its Particular Efficacy in HER2-Amplified Tumors and in Combination Therapies
Tamara Zenz, Robert Jenke, René Thieme, Tim Kahl, Hannes Borchardt, Ines Gockel, Finn K. Hansen, Achim Aigner, Thomas R. H. Büch
Received June 10, 2024  Accepted November 28, 2024  Published online December 10, 2024  
DOI: https://doi.org/10.4143/crt.2024.546    [Epub ahead of print]
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Human epidermal growth factor receptor 2 (HER2) inhibition represents a therapeutic approach with proven clinical efficacy in gastric cancer. However, resistance against HER2-directed therapeutics highlights the need for alternative approaches or drug combinations. Histone deacetylase inhibitors (HDACi) display a broad spectrum of antitumor properties, which may include effects on receptor tyrosine kinases.
Materials and Methods
We analyzed the effects of the class I HDACi entinostat in a panel of HER2-amplified and non-amplified gastric adenocarcinoma cells in 2D cell culture as well as in tumor slice models ex vivo and in patient-derived xenografts in vivo. Effects on protein expression/signal transduction were evaluated by immunoblotting and quantitative reverse transcription polymerase chain reaction.
Results
HDAC inhibition reduced HER2 protein expression independently of initial HER2 expression levels. This was associated with the upregulation of the HER2-inhibiting microRNA miR-205. The downregulation of HER2 resulted in reduced AKT phosphorylation, apoptosis induction and antiproliferative effects, with particularly high efficiency in HER2-amplified gastric cancer cells. Inhibiting HER2 by a specific kinase inhibitor in gastric cancer cells with low basal HER2 expression led to HER2 upregulation. This was reversed by entinostat treatment and provided the basis for synergistic cell inhibition upon double treatment.
Conclusion
We describe the downregulation of HER2 in gastric carcinoma cells upon HDACi treatment. Concomitantly, cells with high basal or treatment-induced HER2 expression showed most profound sensitivities towards HDACi. These findings may thus provide the basis for HDACi treatment as a therapeutic option particularly valuable in HER2-amplified gastric cancer and particularly useful in combination therapies with HER2 inhibitors.

Citations

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  • Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat
    Tamara Zenz, Robert Jenke, Denys Oliinyk, Sandra Noske, René Thieme, Tim Kahl, Ines Gockel, Florian Meier-Rosar, Achim Aigner, Thomas RH Büch
    Neoplasia.2025; 60: 101121.     CrossRef
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  • 101 Download
  • 1 Crossref
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CNS cancer
Hypo-trimethylation of Histone H3 Lysine 4 and Hyper-tri/dimethylation of Histone H3 Lysine 27 as Epigenetic Markers of Poor Prognosis in Patients with Primary Central Nervous System Lymphoma
Hoon Gi Kim, Minseok S. Kim, Young Sam Lee, Eun Hee Lee, Dae Cheol Kim, Sung-Hun Lee, Young Zoon Kim
Cancer Res Treat. 2022;54(3):690-708.   Published online November 17, 2021
DOI: https://doi.org/10.4143/crt.2021.1121
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study aimed to investigate the methylation status of major histone modification sites in primary central nervous system lymphoma (PCNSL) samples and examine their prognostic roles in patients with PCNSL.
Materials and Method
Between 2007 and 2020, 87 patients were histopathologically diagnosed with PCNSL. We performed immunohistochemical staining of the formalin-fixed paraffin-embedded samples of PCNSL for major histone modification sites, such as H3K4, H3K9, H3K27, H3K14, and H3K36. After detection of meaningful methylation sites, we examined histone modification enzymes that induce methylation or demethylation at each site using immunohistochemical staining. The meaningful immunoreactivity was validated by western blotting using fresh tissue of PCNSL.
Results
More frequent recurrences were found in hypomethylation of H3K4me3 (p=0.004) and hypermethylation of H3K27me2 (p<0.001) and H3K27me3 (p=0.002). These factors were also statistically related to short PFS and overall survival in the univariate and multivariate analyses. Next, histone modification enzymes inducing the demethylation of H3K4 (lysine-specific demethylase-1/2 and Jumonji AT-rich interactive domain [JARID] 1A-D]) and methylation of H3K27 (enhancer of zeste homolog [EZH]-1/2) were immu- nohistochemically stained. Among them, the immunoreactivity of JARID1A inversely associated with the methylation status of H3K4me3 (R2=-1.431), and immunoreactivity of EZH2 was directly associated with the methylation status of H3K27me2 (R2=0.667) and H3K27me3 (R2=0.604). These results were validated by western blotting in fresh PCNSL samples.
Conclusion
Our study suggests that hypomethylation of H3K4me3 and hypermethylation of H3K27me2 and H3K27me3 could be associated with poor outcomes in patients with PCNSL and that these relationships are modified by JARID1A and EZH2.

Citations

Citations to this article as recorded by  
  • Updates of primary central nervous system lymphoma
    Jiaying Wu, Delian Zhou, Xiaojian Zhu, Yicheng Zhang, Yi Xiao
    Therapeutic Advances in Hematology.2024;[Epub]     CrossRef
  • 3-deazaneplanocin A, a histone methyltransferase inhibitor, improved the chemoresistance induced under hypoxia in melanoma cells
    Mika Hosokawa, Sekai Tetsumoto, Mirano Yasui, Yusuke Kono, Ken-ichi Ogawara
    Biochemical and Biophysical Research Communications.2023; 677: 26.     CrossRef
  • Extranodal lymphoma: pathogenesis, diagnosis and treatment
    Hua Yang, Yang Xun, Chao Ke, Kensuke Tateishi, Hua You
    Molecular Biomedicine.2023;[Epub]     CrossRef
  • Diagnostic and Therapeutic Perspectives Associated to Cobalamin-Dependent Metabolism and Transcobalamins’ Synthesis in Solid Cancers
    Valentin Lacombe, Guy Lenaers, Geoffrey Urbanski
    Nutrients.2022; 14(10): 2058.     CrossRef
  • Primary central nervous system lymphoma: advances in its pathogenesis, molecular markers and targeted therapies
    Isaias Hernández-Verdin, Andrea Morales-Martínez, Khê Hoang-Xuan, Agustí Alentorn
    Current Opinion in Neurology.2022; 35(6): 779.     CrossRef
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Lung and Thoracic cancer
Histone Deacetylase as a Valuable Predictive Biomarker and Therapeutic Target in Immunotherapy for Non-Small Cell Lung Cancer
Hyun-Seock Shin, Juwhan Choi, Jinhwan Lee, Sung Yong Lee
Cancer Res Treat. 2022;54(2):458-468.   Published online September 10, 2021
DOI: https://doi.org/10.4143/crt.2021.425
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Histone deacetylase inhibitors (HDACis) are epigenetic regulators and used clinically for hematopoietic malignancies. Recently, HDACis have received attention as a factor that modulates the immune system. In this study, the role of histone deacetylase (HDAC) expression as a predictive marker in lung cancer patients who were treated with immune checkpoint inhibitors (ICIs) and the role of HDACi and ICI combination treatment in the mouse tumor model were analyzed.
Materials and Methods
The overall response rate (ORR) and progression-free survival (PFS) were analyzed by the expression of HDAC. In vitro assay, the mRNA and protein expression levels of cytokines and programmed death-ligand 1 (PD-L1) were analyzed after HDACi treatment. In vivo assay, TC-1 tumor-bearing mice were treated with HDACi and mouse programmed cell death 1 (PD-1) inhibitor.
Results
The HDAC6 low expression group showed high ORR and prolonged PFS. When the selective HDAC6 inhibitor was administered to the A549 cell line, the levels of interleukin-1β and interleukin-6 decreased and the expression of PD-L1 was reduced. Mice that received both the mouse PD-1 inhibitor and pan-HDACi had a smaller tumor size than that of the mice from the control group. Moreover, mice treated with the mouse PD-1 inhibitor and pan-HDACi generated greater numbers of E7-specific CD8+ T cells.
Conclusion
HDAC6 expression can predict the prognosis of non–small cell lung cancerpatients who were treated with ICIs. Furthermore, co-treatment with HDACi and PD-1 inhibitor was shown to decrease the tumor growth rate and create a favorable tumor microenvironment for cytotoxic T lymphocytes in the TC-1 mouse model.

Citations

Citations to this article as recorded by  
  • Lysosomes: guardians and healers within cells- multifaceted perspective and outlook from injury repair to disease treatment
    Jianlei Bi, Yincong Sun, Meihua Guo, Xiaoxin Sun, Jie sun, Rujiao Jiang, Ning Wang, Gena Huang
    Cancer Cell International.2025;[Epub]     CrossRef
  • Recent advances in biomarkers for predicting the efficacy of immunotherapy in non-small cell lung cancer
    Jiacheng Zhang, Zehao Song, Yuanjie Zhang, Chentong Zhang, Qi Xue, Guochao Zhang, Fengwei Tan
    Frontiers in Immunology.2025;[Epub]     CrossRef
  • Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy
    Lisa K Poppe, Nicholas Roller, Miriam Marlene Medina-Enriquez, Wiem Lassoued, Daniel Burnett, Katherine E Lothstein, Asma S Khelifa, Masaya Miyamoto, James L Gulley, Caroline Jochems, Jeffrey Schlom, Sofia R Gameiro
    Journal for ImmunoTherapy of Cancer.2025; 13(5): e011074.     CrossRef
  • Histone modifications and metabolic reprogramming in tumor-associated macrophages: a potential target of tumor immunotherapy
    Yiting Xu, Han Zhang, Dengyun Nie
    Frontiers in Immunology.2025;[Epub]     CrossRef
  • Death-ision: the link between cellular resilience and cancer resistance to treatments
    Gustavo Baldassarre, Ivana L. de la Serna, François M. Vallette
    Molecular Cancer.2025;[Epub]     CrossRef
  • Immunomodulatory properties of HDAC6 inhibitors in cancer diseases: New chances for sophisticated drug design and treatment optimization
    Bernhard Biersack, Bianca Nitzsche, Michael Höpfner
    Seminars in Cell & Developmental Biology.2024; 154: 286.     CrossRef
  • Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1
    Ana Dillen, Indy Bui, Megan Jung, Stephanie Agioti, Apostolos Zaravinos, Benjamin Bonavida
    Cancers.2024; 16(6): 1237.     CrossRef
  • Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway
    Zhijie Wang, Lin Yuan, Xiaotong Liao, Xia Guo, Jianjun Chen
    Journal of Medicinal Chemistry.2024; 67(8): 6027.     CrossRef
  • Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells
    Sarah Ducellier, Mélanie Demeules, Boris Letribot, Massimiliano Gaetani, Chloé Michaudel, Harry Sokol, Abdallah Hamze, Mouad Alami, Mégane Nascimento, Sébastien Apcher
    Journal for ImmunoTherapy of Cancer.2024; 12(4): e007588.     CrossRef
  • Selective HDAC6 Inhibition Has the Potential for Anti-Cancer Effect in Renal Cell Carcinoma
    Tsutomu Anraku, Masaki Murata, Hiroo Kuroki, Akira Kazama, Yuko Shirono, Masayuki Tasaki, Vladimir Bilim, Yoshihiko Tomita
    Journal of Personalized Medicine.2024; 14(7): 704.     CrossRef
  • Histone deacetylase inhibitors for leukemia treatment: current status and future directions
    Mohammad-Salar Hosseini, Zohreh Sanaat, Mohammad Amin Akbarzadeh, Yosra Vaez-Gharamaleki, Mahsa Akbarzadeh
    European Journal of Medical Research.2024;[Epub]     CrossRef
  • Epigenetic Modification of PD-1/PD-L1-Mediated Cancer Immunotherapy against Melanoma
    Hikaru Nanamori, Yu Sawada
    International Journal of Molecular Sciences.2022; 23(3): 1119.     CrossRef
  • Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer
    Shuo Yang, Yang Huang, Qi Zhao
    Frontiers in Immunology.2022;[Epub]     CrossRef
  • Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance
    Hyein Jo, Kyeonghee Shim, Dooil Jeoung
    International Journal of Molecular Sciences.2022; 23(17): 9592.     CrossRef
  • Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)
    Xiaoran Ma, Jibiao Wu, Bin Wang, Cun Liu, Lijuan Liu, Changgang Sun
    International Journal of Oncology.2022;[Epub]     CrossRef
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Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy
Erta Kalanxhi, Karianne Risberg, Imon S. Barua, Svein Dueland, Stein Waagene, Solveig Norheim Andersen, Solveig J. Pettersen, Jessica M. Lindvall, Kathrine Røe Redalen, Kjersti Flatmark, Anne Hansen Ree
Cancer Res Treat. 2017;49(2):374-386.   Published online July 28, 2016
DOI: https://doi.org/10.4143/crt.2016.080
AbstractAbstract PDFPubReaderePub
Purpose
When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser.
Materials and Methods
This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA.
Results
PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss.
Conclusion
The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.

Citations

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    Yinlong Zhao, Shirui Liu, Yu Wen, Lili Zhong
    Gynecologic and Obstetric Investigation.2021; 86(1-2): 71.     CrossRef
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    Félix G. Delgado, Paola Cárdenas, Jaime E. Castellanos
    Diseases.2018; 6(3): 59.     CrossRef
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    Silmara N. Andrade, Fernanda C. G. Evangelista, Diego Seckler, Deisielly R. Marques, Túlio R. Freitas, Renata R. Nunes, Júlia T. Oliveira, Rosy I. M. A. Ribeiro, Hélio B. Santos, Ralph G. Thomé, Alex G. Taranto, Fabio V. Santos, Gustavo H. R. Viana, Rossi
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    Blaz Groselj, Jia-Ling Ruan, Helen Scott, Jessica Gorrill, Judith Nicholson, Jacqueline Kelly, Selvakumar Anbalagan, James Thompson, Michael R.L. Stratford, Sarah J. Jevons, Ester M. Hammond, Cheryl L. Scudamore, Martin Kerr, Anne E. Kiltie
    Molecular Cancer Therapeutics.2018; 17(2): 381.     CrossRef
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  • 4 Web of Science
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Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041
Jin Ho Kim, Il Han Kim, Jin Hee Shin, Hak Jae Kim, In Ah Kim
Cancer Res Treat. 2013;45(4):334-342.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.334
AbstractAbstract PDFPubReaderePub
PURPOSE
This preclinical study is to determine whether the capacity of histone deacetylase (HDAC) inhibitors to enhance radiation response depends on temporal sequences of HDAC inhibition and irradiation.
MATERIALS AND METHODS
The effects of HDAC inhibitors trichostatin A (TSA) and SK-7041 on radiosensitivity in human lung cancer cells were examined using a clonogenic assay, exposing cells to HDAC inhibitors in various sequences of HDAC inhibition and radiation. We performed Western blot of acetylated histone H3 and flow cytometry to analyze cell cycle phase distribution.
RESULTS
TSA and SK-7041 augmented radiation cell lethality in an exposure time-dependent manner when delivered before irradiation. The impact of TSA and SK-7041 on radiosensitivity rapidly diminished when HDAC inhibition was delayed after irradiation. Radiation induced the acetylation of histone H3 in cells exposed to TSA, while irradiation alone had no effect on the expression of acetylated histone H3 in TSA-naive cells. Preirradiation exposure to TSA abrogated radiation-induced G2/M-phase arrest. When delivered after irradiation, TSA had no effect on the peak of radiation-induced G2/M-phase arrest.
CONCLUSION
TSA and SK-7041 enhances radiosensitivity only when delivered before irradiation. Unless proven otherwise, it seems prudent to apply scheduling including preirradiation HDAC inhibition so that maximal radiosensitization is obtained.

Citations

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  • Mechanistic Sequence of Histone Deacetylase Inhibitors and Radiation Treatment: An Overview
    Elsie Neo Seane, Shankari Nair, Charlot Vandevoorde, Anna Joubert
    Pharmaceuticals.2024; 17(5): 602.     CrossRef
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    N. Ulyasheva, E. Proshkina, M. Shaposhnikov, A. Moskalev
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    Fengqiu Zhang, Changsheng Shao, Zhu Chen, Yalin Li, Xumiao Jing, Qing Huang
    Radiation Research.2021;[Epub]     CrossRef
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    Fengqiu Zhang, Zhu Chen, Changsheng Shao, Qing Huang
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis.2019; 813: 13.     CrossRef
  • Disulfiram, a Re-positioned Aldehyde Dehydrogenase Inhibitor, Enhances Radiosensitivity of Human Glioblastoma Cells In Vitro
    Hyeon Kang Koh, Soo Yeon Seo, Jin Ho Kim, Hak Jae Kim, Eui Kyu Chie, Seung-Ki Kim, Il Han Kim
    Cancer Research and Treatment.2019; 51(2): 696.     CrossRef
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    Chan Woo Wee, Jin Ho Kim, Hak Jae Kim, Hyun-Cheol Kang, Soo Youn Suh, Beom Soo Shin, Eunsook Ma, Il Han Kim
    Journal of Radiation Protection and Research.2019; 44(1): 15.     CrossRef
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    Jin Ho Kim, Sung Ho Moon, Mina No, Jae Jin Kim, Eun Jung Choi, Bong Jun Cho, Jae Sung Kim, Il Han Kim, In Ah Kim
    Cancer Research and Treatment.2016; 48(3): 1130.     CrossRef
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A Histone Deacetylase Inhibitor, Trichostatin A, Enhances Radiosensitivity by Abrogating G2/M Arrest in Human Carcinoma Cells
In Ah Kim, Jin Ho Kim, Jin Hee Shin, Il Han Kim, Jae Sung Kim, Hong-Gyun Wu, Eui Kyu Chie, Yong Ho Kim, Bo-Kyung Kim, Semie Hong, Seok Won Park, Sung Whan Ha, Charn Il Park
Cancer Res Treat. 2005;37(2):122-128.   Published online April 30, 2005
DOI: https://doi.org/10.4143/crt.2005.37.2.122
AbstractAbstract PDFPubReaderePub
Purpose

Histone deacetylase inhibitors (HDIs) are emerging as potentially useful components in anticancer therapy. In this study, we tried to confirm the radiosensitizing effect of trichostatin A (TSA) on a panel of human carcinoma cell lines and elucidate its mechanism of interaction.

Materials and Methods

A549, HeLa and Caski cells were exposed to TSA for 18 hr prior to irradiation, and the cell survival then measured using a clonogenic assay. Western blot and flow cytometric analyses, for histone acetylation, and cell cycle and apoptosis, respectively, were also performed.

Results

TSA increased the acetylation of histone H3. The pretreatment of TSA consistently radiosensitized all three cell lines. The SF2 (surviving fraction at 2 Gy) of TSA-treated cells was significantly lower than that of mock treated cells. The SER (sensitizer enhancement ratio) increased in all 3 cell lines, in concentration dependent manners. The TSA treated cells showed abrogation of radiation-induced G2/M arrest, in a concentration dependent manner.

Conclusion

The pretreatment of TSA enhanced the radiosensitivity of a panel of human carcinoma cells, which was attributed, in part, to the abrogation of radiation-induced G2/M arrest.

Citations

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    Yijun Xie, Di Xiao, Duo Li, Mei Peng, Wei Peng, Huaxin Duan, Xiaoping Yang
    Frontiers in Oncology.2024;[Epub]     CrossRef
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    Abdelhakim Bouyahya, Nasreddine El Omari, Mohamed Bakha, Tarik Aanniz, Naoual El Menyiy, Naoufal El Hachlafi, Aicha El Baaboua, Mohamed El-Shazly, Mohammed Merae Alshahrani, Ahmed Abdullah Al Awadh, Learn-Han Lee, Taoufiq Benali, Mohammad S. Mubarak
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    Radiation Research.2021;[Epub]     CrossRef
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    Ahrum Min, Seock-Ah Im, Debora Keunyoung Kim, Sang-Hyun Song, Hee-Jun Kim, Kyung-Hun Lee, Tae-Yong Kim, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Mark J O’Connor, Yung-Jue Bang
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    In Ah Kim, Jin Hee Shin, Il Han Kim, Jin Ho Kim, Jae Sung Kim, Hong Gyun Wu, Eui Kyu Chie, Sung Whan Ha, Charn Il Park, Gary D. Kao
    Clinical Cancer Research.2006; 12(3): 940.     CrossRef
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Transcriptional Regulation of H2B Histone Gene Expression by Nocodazole in HL-60 Cells
Kyu Lim, Ye Gi Hong, Myung Sun Lee, Mee Young Son, Kyung Ah Yun, Jong Il Park, Wan Hee Yoon, Sung Kiel Park, Byung Doo Hwang
J Korean Cancer Assoc. 2000;32(2):407-416.
AbstractAbstract PDF
PURPOSE
Nocodazole, a microtubule disrupting reagent, is known to arrest cells in the M phase, To gain insight on the regulatory mechanism of H2B histone gene expression by nocodazole in HL-60 cell, the binding pattern of nuclear proteins to cis element in the human H2B histone gene promoter has been investigated with DNase I footprinting and DNA mobility shift assay.
MATERIALS AND METHODS
Northern blot hybridization was performed by the method of Virca et al. A Hinc II-Sac I fragment of pSPH28 was used as probe for Northern blot analysis of H2B histone mRNA. DNase I footprinting and DNA mobility shift assay were performed by the method of Lim et al. End labeled DNA oligomer (upper strand, 5'-CTTCACCTTATTTGCATAA GCGATTC-3') for octamer binding activity was mixed with nuclear extracts in a 20 ul reaction volume containing 60 mM KC1, 12 mM HEPES, pH 7.9, 5 mM MgCl2, 0.2 mM EDTA, 0.2 mM DTT, 12% glycerol, and 2 ug of poly [dI-dC].
RESULTS
The level of H2B histone mRNA rapidly was reduced at 24 hours in nocodazole-treated HL-60 cells and the mRNA was repressed in proportion to the concentration of nocodazole. Nocodazole-dependent repression of H2B histone gene was restored by replacement with nocodazole-free media. In DNase I footprinting analysis, one nuclear factor bound at 42 bp site (octamer motif) in the absence of nocodazole. In the presence of nocodazole, the binding of nuclear factor on octamer motif partially vanished. In DNA mobility shift assay, one DNA-protein complex (Octl) was formed when octamer motif was incubated with nuclear extract of HL-60 cell. After nocodazole treatment, Octl binding activity was reduced by time dependent manner.
CONCLUSION
These results suggest that nocodazole-dependent repression of H2B histone gene is correlated with reduction of Octl binding activity in HL-60 cell.
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Studies on the H2B Histone , c-Myc and DNA Topoisomerase 1 Gene Expression during HL - 60 Differentiation by All - Trans Retinoic Acid
Kyu Lim, Jeong Dong Park, Byung Han Choi, Young Jin Lee, Kye Young Kim, Myung Sun Lee, Eun Mi Chang, Sam Yong Kim, Gi Ryang Kweon, Sang Tae Kwak, Byung Doo Hwang
J Korean Cancer Assoc. 1994;26(2):285-296.
AbstractAbstract PDF
Effects of all-trans retinoic acid(retinoic acid) on DNA replication, H2B histone and DNA topoisopmerase I(Topo I) gene expression have been investigated in human promyelocytic leukemia cell line HL-60. DNA synthesis decreased at 24 hours after exposure of retinoic acid in the HL-60 cells. H2B histone mRNA rapidly reduced at 48 hours and Topo I and c-myc mRNA at 24 hours in retinoic acid-exposured HL-60 cells, respectively. The levels of c-myc, H2B his- tone and Topo I gene expression were reduced in proportion to the concentration of retinoic acid. The H2B histone mRNA in retinoic acid-exposured cells was elevated by cycloheximide treatment, while the level of Topo I mRNA was constant. These results suggest that regulations of H2B histone, c-myc and Topo I gene expression are different from one another, and repression of Topo I gene is closely correlated with c-myc gene during retinoic acid-induced differentiation of HL-60 cells.
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Prognostic Significance of Tumor Angiogenesis , Metastasis Regulation Gene Protein ( NDP-K / nm23 ) and Histone mRNA Expression in Breast Cancer
Hye Rim Park, Young Sik Kim, In Sun Kim
J Korean Cancer Assoc. 1995;27(2):253-265.
AbstractAbstract PDF
Tumor angiogenesis and expression of metastasis regulation gene protein(nm23) and histone mRNA were eveluated in 42 breast cancers to assess their roles in prognosis. Tumor angiogenesis was studied by measuring the FVIIIRA-positive endothelial cells, and nm23 protein expression by immunohistochemical staining. Histone mRNA poisitive cells were examined by non-isotopic in situ hybridization. The results were analyzed according to the patients age, tumor size, presence or absence of lymph node metastais and DNA ploidy. DNA aneuploidy was found in 28 of 38 (74%) and Factor VIIIRA-positive endothelial cells were found within and around the invasive carcinoma and periductal stroma in intraductal carcinoma. Tumor angiogenesis was more active in primary tumors than in metastatic lesions. nm23 protein expresian was strong in normal parenchyme, but it was variable in stainability and extents according to the areas. The intraductal component showed stronger staining than invasive carcinoma in nm23 protein expression. Histone mRNA positive cells were found in both normal and malignant epithelial cells, but more frequent in metastatic lesion than in primary tumor. Tumor angiogenesis and loss of nm23 protein were associated with the presence of metastatic node and large size of primary tumor(23 cm). The expression of histone mRNA was only associated with poor differentiation af tumor, but not with S-phase fraction af cell cycle study. From this study, it is concluded that tumor angiogenesis and expression of nm23 protein could be used as prognostic indicators in breast cancers, but histone mRNA expression had the limited value.
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Cancer Res Treat : Cancer Research and Treatment
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