Cancer Research and Treatment

Original Articles

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]

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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.

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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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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

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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

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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

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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

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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

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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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Effect of MicroRNA-210 on the Growth of Ovarian Cancer Cells and the Efficacy of Radiotherapy
Yinlong Zhao, Shirui Liu, Yu Wen, Lili Zhong
Gynecologic and Obstetric Investigation.2021; 86(1-2): 71. CrossRef
Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus
Félix G. Delgado, Paola Cárdenas, Jaime E. Castellanos
Diseases.2018; 6(3): 59. CrossRef
Synthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs
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
Medicinal Chemistry Research.2018; 27(11-12): 2397. CrossRef
Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity
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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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

Abstract PDF PubReader ePub

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
Investigation of geroprotective and radioprotective effects of berberine and trichostatin A on the model of Drosophila melanogaster
N. Ulyasheva, E. Proshkina, M. Shaposhnikov, A. Moskalev
Proceedings of the Komi Science Centre of the Ural Division of the Russian Academy of Sciences.2023; 0(6): 93. CrossRef
Low Dose of Trichostatin A Improves Radiation Resistance by Activating Akt/Nrf2-Dependent Antioxidation Pathway in Cancer Cells
Fengqiu Zhang, Changsheng Shao, Zhu Chen, Yalin Li, Xumiao Jing, Qing Huang
Radiation Research.2021;[Epub] CrossRef
Time-sequential change in immune-related gene expression after irradiation in glioblastoma: next-generation sequencing analysis
Yi-Jun Kim, Kwangsoo Kim, Soo Yeon Seo, Juyeon Yu, Il Han Kim, Hak Jae Kim, Chul-Kee Park, Kye Hwa Lee, Junjeong Choi, Myung Seon Song, Jin Ho Kim
Animal Cells and Systems.2021; 25(4): 245. CrossRef
Is level of acetylation directly correlated to radiation sensitivity of cancer cell?
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
Psammaplin A-Modified Novel Radiosensitizers for Human Lung Cancer and Glioblastoma Cells
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
Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization
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

Abstract PDF PubReader ePub

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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Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer
Yijun Xie, Di Xiao, Duo Li, Mei Peng, Wei Peng, Huaxin Duan, Xiaoping Yang
Frontiers in Oncology.2024;[Epub] CrossRef
Radiosensitizing effect of dendrosomal nanoformulation of curcumin on cancer cells
Tahereh Jalali Varnamkhasti, Meisam Jafarzadeh, Majid Sadeghizadeh, Mahdi Aghili
Pharmacological Reports.2022; 74(4): 718. CrossRef
Pharmacological Properties of Trichostatin A, Focusing on the Anticancer Potential: A Comprehensive Review
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
Pharmaceuticals.2022; 15(10): 1235. CrossRef
Low Dose of Trichostatin A Improves Radiation Resistance by Activating Akt/Nrf2-Dependent Antioxidation Pathway in Cancer Cells
Fengqiu Zhang, Changsheng Shao, Zhu Chen, Yalin Li, Xumiao Jing, Qing Huang
Radiation Research.2021;[Epub] CrossRef
Targeted Therapeutic Strategies for Triple-Negative Breast Cancer
Ying Li, Zhijun Zhan, Xuemin Yin, Shujun Fu, Xiyun Deng
Frontiers in Oncology.2021;[Epub] CrossRef
Is level of acetylation directly correlated to radiation sensitivity of cancer cell?
Fengqiu Zhang, Zhu Chen, Changsheng Shao, Qing Huang
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis.2019; 813: 13. CrossRef
Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53
Manuela Terranova-Barberio, Biagio Pecori, Maria Serena Roca, Serena Imbimbo, Francesca Bruzzese, Alessandra Leone, Paolo Muto, Paolo Delrio, Antonio Avallone, Alfredo Budillon, Elena Di Gennaro
Journal of Experimental & Clinical Cancer Research.2017;[Epub] CrossRef
Histone Acetylation Induced Transformation of B-DNA to Z-DNA in Cells Probed through FT-IR Spectroscopy
Fengqiu Zhang, Qing Huang, Jingwen Yan, Zhu Chen
Analytical Chemistry.2016; 88(8): 4179. CrossRef
Cell-based multi-substrate assay coupled to UHPLC-ESI-MS/MS for a quick identification of class-specific HDAC inhibitors
Vincent Zwick, Claudia Simões-Pires, Muriel Cuendet
Journal of Enzyme Inhibition and Medicinal Chemistry.2016; 31(sup1): 209. CrossRef
Assessment of the Effect of Trichostatin A on HeLa Cells through FT-IR Spectroscopy
Fengqiu Zhang, Qing Huang, Jingwen Yan, Xin Zhang, Jianxin Li
Analytical Chemistry.2015; 87(4): 2511. CrossRef
Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells
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
Breast Cancer Research.2015;[Epub] CrossRef
CD44 is a biomarker associated with human prostate cancer radiation sensitivity
WeiWei Xiao, Peter H. Graham, Carl A. Power, Jingli Hao, John H. Kearsley, Yong Li
Clinical & Experimental Metastasis.2012; 29(1): 1. CrossRef
Identification of a radiosensitivity signature using integrative metaanalysis of published microarray data for NCI-60 cancer cells
Han Sang Kim, Sang Cheol Kim, Sun Jeong Kim, Chan Hee Park, Hei-Cheul Jeung, Yong Bae Kim, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha
BMC Genomics.2012;[Epub] CrossRef
In vivoRadiosensitization Effect of HDAC Inhibitor, SK-7041 on RIF-1 Cell Line
Eui Kyu Chie, Jin Hee Shin, In Ah Kim, Il Han Kim
The Journal of the Korean Society for Therapeutic Radiology and Oncology.2010; 28(4): 219. CrossRef
Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: Potential role of histone deacetylase 6
In Ah Kim, Mina No, Jang Mi Lee, Jin Hee Shin, Jee Sun Oh, Eun Jung Choi, Il Han Kim, Peter Atadja, Eric J. Bernhard
Radiotherapy and Oncology.2009; 92(1): 125. CrossRef
Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53
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.

Abstract 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.

Abstract 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.

Abstract 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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