EZH2: a Novel Target for Cancer Treatment

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2020 Jul 30

PMID 32723346

Citations 352

Authors

Ran Duan

Wenfang Du

Weijian Guo

Affiliations

Soon will be listed here.

Abstract

Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-to-date findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.

Citing Articles

Epigenetic regulatory protein chromobox family regulates multiple signalling pathways and mechanisms in cancer.

Su W, Wang W, Zhang G, Yang L Clin Epigenetics. 2025; 17(1):48.

PMID: 40083014 PMC: 11907984. DOI: 10.1186/s13148-025-01852-w.

Putative Epigenetic Regulator microRNAs (epi-miRNAs) and Their Predicted Targets in High-Fat Diet-Induced Cardiac Dysfunction: An In Silico Analysis in Obese Rats.

Pipicz M, Biro G, Szabo M, Zvara A, Csont T Int J Mol Sci. 2025; 26(5).

PMID: 40076868 PMC: 11900980. DOI: 10.3390/ijms26052247.

Validation of the International Medullary Thyroid Cancer Grading System and Identification of EZH2 as a Prognostic and Potential Therapeutic Marker in Medullary Thyroid Cancer.

Jager E, van Hemel B, Rutgers B, Zandee W, Jansen L, Kruijff S Cancers (Basel). 2025; 17(5).

PMID: 40075585 PMC: 11899120. DOI: 10.3390/cancers17050737.

Increasing RB1 Expression by Targeting EZH2 in Triple-Negative Breast Cancer.

Yang R, Fei L, Xue Y, Zhang Y, Hu Q, Guo L J Cell Mol Med. 2025; 29(5):e70384.

PMID: 40070134 PMC: 11897054. DOI: 10.1111/jcmm.70384.

Overcoming drug resistance in castrate-resistant prostate cancer: current mechanisms and emerging therapeutic approaches.

Khorasanchi A, Hong F, Yang Y, Singer E, Wang P, Li M Cancer Drug Resist. 2025; 8:9.

PMID: 40051495 PMC: 11883235. DOI: 10.20517/cdr.2024.173.

References

Sarkozy C, Morschhauser F, Dubois S, Molina T, Michot J, Cullieres-Dartigues P . A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features. Clin Cancer Res. 2020; 26(13):3145-3153. DOI: 10.1158/1078-0432.CCR-19-3741. View

Fioravanti R, Stazi G, Zwergel C, Valente S, Mai A . Six Years (2012-2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2-Pyridone Compounds. Chem Rec. 2018; 18(12):1818-1832. PMC: 7410397. DOI: 10.1002/tcr.201800091. View

Zhang P, Xiao Z, Wang S, Zhang M, Wei Y, Hang Q . ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer. Cell Rep. 2018; 23(3):823-837. PMC: 5933875. DOI: 10.1016/j.celrep.2018.03.078. View

Wang X, Wang C, Zhang X, Hua R, Gan L, Huang M . Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs. J Hematol Oncol. 2016; 9(1):90. PMC: 5029045. DOI: 10.1186/s13045-016-0323-9. View

Goswami S, Apostolou I, Zhang J, Skepner J, Anandhan S, Zhang X . Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest. 2018; 128(9):3813-3818. PMC: 6118570. DOI: 10.1172/JCI99760. View

Zhu M, Du D, Hu J, Li L, Liu J, Ding H . Development of a high-throughput fluorescence polarization assay for the discovery of EZH2-EED interaction inhibitors. Acta Pharmacol Sin. 2017; 39(2):302-310. PMC: 5800469. DOI: 10.1038/aps.2017.59. View

Katona B, Liu Y, Ma A, Jin J, Hua X . EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells. Cancer Biol Ther. 2014; 15(12):1677-87. PMC: 4622469. DOI: 10.4161/15384047.2014.972776. View

Wang X, Cao W, Zhang J, Yan M, Xu Q, Wu X . A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination. EMBO J. 2017; 36(9):1243-1260. PMC: 5412902. DOI: 10.15252/embj.201694058. View

Kim J, Lee Y, Lu X, Song B, Fong K, Cao Q . Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator. Cell Rep. 2018; 25(10):2808-2820.e4. PMC: 6342284. DOI: 10.1016/j.celrep.2018.11.035. View

10.

Zhang K, Shen Q, Fang Y, Sun Y, Ding J, Chen Y . AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition. Acta Pharmacol Sin. 2019; 40(12):1587-1595. PMC: 7468275. DOI: 10.1038/s41401-019-0248-2. View

11.

Ito T, Teo Y, Evans S, Neretti N, Sedivy J . Regulation of Cellular Senescence by Polycomb Chromatin Modifiers through Distinct DNA Damage- and Histone Methylation-Dependent Pathways. Cell Rep. 2018; 22(13):3480-3492. PMC: 5915310. DOI: 10.1016/j.celrep.2018.03.002. View

12.

Italiano A . Targeting epigenetics in sarcomas through EZH2 inhibition. J Hematol Oncol. 2020; 13(1):33. PMC: 7140314. DOI: 10.1186/s13045-020-00868-4. View

13.

Qiu B, Lin X, Ye X, Huang W, Pei X, Xiong D . Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA. Aging (Albany NY). 2020; 12(2):1843-1856. PMC: 7053621. DOI: 10.18632/aging.102716. View

14.

Huang S, Wang Z, Zhou J, Huang J, Zhou L, Luo J . EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells. Cancer Res. 2019; 79(8):2009-2020. DOI: 10.1158/0008-5472.CAN-18-2395. View

15.

Kleer C, Cao Q, Varambally S, Shen R, Ota I, Tomlins S . EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003; 100(20):11606-11. PMC: 208805. DOI: 10.1073/pnas.1933744100. View

16.

Lu W, Liu S, Li B, Xie Y, Izban M, Ballard B . SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer. Oncogene. 2016; 36(10):1364-1373. PMC: 5724960. DOI: 10.1038/onc.2016.300. View

17.

Mallen-St Clair J, Soydaner-Azeloglu R, Lee K, Taylor L, Livanos A, Pylayeva-Gupta Y . EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev. 2012; 26(5):439-44. PMC: 3305982. DOI: 10.1101/gad.181800.111. View

18.

Li H, Wen Y, Wu S, Chen D, Luo X, Xu R . Epigenetic Modification of Enhancer of Zeste Homolog 2 Modulates the Activation of Dendritic Cells in Allergen Immunotherapy. Int Arch Allergy Immunol. 2019; 180(2):120-127. DOI: 10.1159/000500882. View

19.

Honma D, Kanno O, Watanabe J, Kinoshita J, Hirasawa M, Nosaka E . Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017; 108(10):2069-2078. PMC: 5623739. DOI: 10.1111/cas.13326. View

20.

Cardoso C, Mignon C, Hetet G, Grandchamps B, Fontes M, Colleaux L . The human EZH2 gene: genomic organisation and revised mapping in 7q35 within the critical region for malignant myeloid disorders. Eur J Hum Genet. 2000; 8(3):174-80. DOI: 10.1038/sj.ejhg.5200439. View