A Review on EZH2 and its Epigenetic Association with Breast Cancer


  • Sandip K. Mishra Cancer Biology Lab, Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha, 751023, India
  • K. Kanchan Cancer Biology Lab, Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha, 751023, India
  • Dharmendra K. Bhargava Cancer Biology Lab, Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha, 751023, India




Breast cancer, tumorigenesis, apoptosis, epigenetic, methylation.


 Enhancer of zeste homolog2 (EZH2), first identified as homolog of the Drosophila enhancer of zeste gene, is histone H3 lysine methyltransferase (H3K27me3), a component of polycomb group proteins (PRC2) that represses the gene expression by modifying the histones epigenetically, thereby silencing developmental regulatory elements in stem as well as cancer cells leading to repression of early differentiation marker genes. Although the mechanistic approach of involving EZH2 to cancer progression has not yet been clearly deciphered, its invasiveness and metastatic potential has been revealed by significant elevation of its expression in normal breast cancer cells after commencement of which a pre-cancerous state was found in morphologically normal breast cancer cells. The tissue microarray analysis of breast carcinomas has shown that EZH2 to be intimately associated with markers of tumor cell proliferation as well as with aggressive diseases. Till now, no demethylating agents have been recommended for treatment of patients, but an in-vitro study using 3-deazaneplanocin, which reduces histone modifications through methylation by reducing the levels of EZH2, has shown a significant reduction in cell proliferation in breast cancer cells. This further signifies the role of EZH2 as a transcriptional repressor. By analyzing methylation profiles of different subtypes of breast cancers like basal-like, luminal A & B, roles of EZH2 have been established in the development of breast cancers. Crosstalk of EZH2 with other silencing/regulating factors like histone deacetylases and miRNAs, have to be considered for evaluating for progression of cell proliferation in different cancer cells including breast cancer.


American Cancer Society. Breast cancer 2012; http://www.cancer.org/Cancer/BreastCancer/DetailedGuide.

Karolina H, Cecilia H, Johan S, Johan Vallon C, Goran J, Hakan O, et al. Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns. Breast Cancer Res 2010; 12: R36. http://dx.doi.org/10.1186/bcr2590

Annika J, Marica V, Martin J, Sven P. Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors. Upsala J Med Sci 2012; 117: 217-24. http://dx.doi.org/10.3109/03009734.2012.659294

Karin C, Geir EE, Jarle A. Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res 2006; 12: 1168-74. http://dx.doi.org/10.1158/1078-0432.CCR-05-1533

Andrew C, Nicholas CP. Aberrations of EZH2 in Cancer. Clin Cancer Res 2011; 17(9): 2613-8. http://dx.doi.org/10.1158/1078-0432.CCR-10-2156

Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002; 9: 419-24.

Kleer CG, Cao Q, Varambally S, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 2003; 100: 11606-11. http://dx.doi.org/10.1073/pnas.1933744100

Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, et al. The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2(2): 84-9. http://dx.doi.org/10.1038/35000034

Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 1998; 392: 190-93. http://dx.doi.org/10.1038/32433

Shiozaki H, Oka H, Inoue M, Tamura S, Monden M. E-cadherin mediated adhesion system in cancer cells. Cancer 1996; 77: 1605-13.

Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani R-S, Tomlins SA, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 2008; 27: 7274-84.

Vleminckx K, Vakaet L Jr., Mareel M, Fiers W, van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991; 66: 107-19. http://dx.doi.org/10.1016/0092-8674(91)90143-M

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. http://dx.doi.org/10.1038/onc.2011.387

Julian P, Rinske D, Xiaoling L, Simon A, Bastiaan E, Paulien CS, et al. BRCA1-deficient mammary tumor cells are dependent on EZH2expression and sensitive to Polycomb Repressive Complex2-inhibitor 3-deazaneplanocin A. Breast Cancer Res 2009; 11: R63. http://dx.doi.org/10.1186/bcr2354

Bediaga NG, Acha-Sagredo A, Guerra I, Viguri A, Albaina C, Diaz IR, et al. DNA methylation epigenotypes in breast cancer molecular subtypes. Breast Cancer Res 2010; 12: R77.

Tang X, Milyavsky M, Shats I, et al. Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene 2004; 23: 5759-69. http://dx.doi.org/10.1038/sj.onc.1207706

Lu C, Han HD, Mangala LS, Ali-Fehmi R, et al. Regulation of Tumor Angiogenesis by EZH2. Cancer Cell 2010; 18: 185-97. http://dx.doi.org/10.1016/j.ccr.2010.06.016

Zhang B, Xiao-Xiao L, Jian-Rong H, Ci-Xiang Z, Meng G, Ming H, Mei-Fang L, et al. Pathologically decreased miR-26a antagonizes apoptosis and facilitates carcinogenesis by targeting MTDH and EZH2 in breast cancer. Carcinogenesis 2011; 32 (1): 2-9. http://dx.doi.org/10.1093/carcin/bgq209

Chang C-J, Yang J-Y, Xia W, Chen C-T, Xie X, Chao C-H, et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling. Cancer Cell 2011; 19(1): 86-100. http://dx.doi.org/10.1016/j.ccr.2010.06.016

Suvà M-L, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle J-C, et al. EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance. Cancer Res 2009; 69: 9211-18. http://dx.doi.org/10.1158/0008-5472.CAN-09-1622

O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T. The Polycomb-Group Gene Ezh2 Is Required for Early Mouse Development. Mol Cell Biol 0270-7306,21.13. 4330-36.

Herrera-Merchan A, Arranz L, Ligos JM, de Molina A, Dominguez O, Gonzalez S. Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat Commun 2012; 3: 623. http://dx.doi.org/10.1038/ncomms1623

Sher F, Rößler R, Brouwer N, Balasubramaniyan V, Boddeke E, Copray S. Differentiation of Neural Stem Cells into Oligodendrocytes: Involvement of the Polycomb Group Protein Ezh2. Stem Cells 2008; 26: 2875-83. http://dx.doi.org/10.1634/stemcells.2008-0121

Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, et al. A protein interaction network for pluripotency of embryonic stem cells. Nature 2006; 444: 364-68. http://dx.doi.org/10.1038/nature05284

Yu YL, Chou RH, Chen LT, Shyu WC, Hsieh SC, Wu CS, et al. EZH2 regulates neuronal differentiation of mesenchymal stem cells through PIP5K1C-dependent calcium signaling. J Biol Chem 2011; 286(11): 9657-67. http://dx.doi.org/10.1074/jbc.M110.185124

Tsang DPF, Cheng ASL. Epigenetic regulation of signaling pathways in cancer: Role of the histone methyltransferase EZH2. J Gastroenterol Hepatol 2011; 26: 19-27. http://dx.doi.org/10.1111/j.1440-1746.2010.06447.x

Min J, Zaslavsky A, Fedele G, et al. An oncogene–tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kB. Nat Med 2010; 16: 286-94. http://dx.doi.org/10.1038/nm.2100

Acharyya S, Sharma SM, Cheng AS, et al. TNF inhibits muscle regeneration by Ezh-2 and Methylation mediated repression of Notch-1: implications in Duchenne muscular dystrophy. PLoSONE (in press).

Wang C, Qi R, Li N, et al. Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. J Biol Chem 2009; 284: 16183-90. http://dx.doi.org/10.1074/jbc.M109.002105

Lee ST, Li Z, Wu Z, Aau M, Guan P, Murthy KRK, et al. Context-Specific Regulation of NF-kB Target Gene Expression by EZH2 in Breast Cancers. Mol Cell 2011; 43: 798-10. http://dx.doi.org/10.1016/j.molcel.2011.08.011

Eberharter A, Becker PB. Histone acetylation: a switch between repressive and permissive chromatin. EMBO Reports 2002; 3: 224-29.

Grimaldi G, Christian M, Steel JH, Henriet P, Poutanen M, Brosens JJ. Down-Regulation of the Histone Methyltransferase EZH2 Contributes to the Epigenetic Programming of Decidualizing Human Endometrial Stromal Cells. Mol Endocrinol 2011; 25(11): 1892-903. http://dx.doi.org/10.1210/me.2011-1139

Boeke J, Regnard C, Cai W, Johansen J, Johansen KM, Becker PB, et al. Phosphorylation of SU(VAR)3–9 by the Chromosomal Kinase JIL-1. PLoS One 2010; 5(4): e10042. http://dx.doi.org/10.1371/journal.pone.0010042

Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28: 1057-68.

Wang H, Wang L, Erdjument Bromage H, Vidal M, Tempst P, Jones RS, et al. Role of histone H2A ubiquitination in polycomb silencing. Nature 2004; 431: 873-78. http://dx.doi.org/10.1038/nature02985

Weiss T, Hergeth S, Zeissler U, Izzo A, Tropberger P, Zee BM, et al. Histone H1 variant-specific lysine methylation by G9a/KMT1C and Glp1/KMT1D. Epigenetics Chromatin 2010; 1186/1756-8935-3-7.

Yamaguchi J, Sasaki M, Sato Y, Itatsu K, Harada K, Zen Y, et al. Histone deacetylase inhibitor (SAHA) and repression of EZH2 synergistically inhibit proliferation of gallbladder carcinoma. Cancer Sci 2010; 101(2): 355-62. http://dx.doi.org/10.1111/j.1349-7006.2009.01387.x

Trojer P, Zhang J, Yonezawa M, Schmidt A, Zheng H, Jenuwein T, et al. Dynamic Histone H1 Isotype 4 Methylation and Demethylation by Histone Lysine Methyltransferase G9a/KMT1C and the Jumonji Domain-containing JMJD2/KDM4 Proteins. J Biol Chem 2009; 284(13): 8395-405. http://dx.doi.org/10.1074/jbc.M807818200

Vire E, et al. The Polycomb group protein EZH2 directly control DNA methylation. Nature 2006; 439(7078): 871-4. http://dx.doi.org/10.1038/nature04431

Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TFE, et al. Pollack, and Thomas Wirth1 MYC stimulate EZH2 expression by repression of its negative regulator miR-26a. Blood 2008; 112: 4202-12.

Jun L, Gad G, Eric AM, Ezequiel AS, Alejandro SC, Benjamin LE, et al. Micro RNA expression profiles classify human cancers. Nature 2005; 435: 834-38.

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(11): 1108-14. http://dx.doi.org/10.1038/ncb2116

Min J, Zaslavsky A, Fedele G, et al. An oncogene–tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kB. Nat Med 2010; 16: 286-94. http://dx.doi.org/10.1038/nm.2100




How to Cite

Sandip K. Mishra, K. Kanchan, & Dharmendra K. Bhargava. (2012). A Review on EZH2 and its Epigenetic Association with Breast Cancer . Journal of Cancer Research Updates, 1(2), 162–172. https://doi.org/10.6000/1929-2279.2012.01.02.2