Repression of E-cadherin by the polycomb group protein EZH2 in cancer

• Published in: Oncogene Vol. 27; no. 58; pp. 7274 - 7284
• Main Authors: Cao, Q, Yu, J, Dhanasekaran, S M, Kim, J H, Mani, R-S, Tomlins, S A, Mehra, R, Laxman, B, Cao, X, Kleer, C G, Varambally, S, Chinnaiyan, A M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-12-2008; Nature Publishing Group
• Subjects: Apoptosis; Benign; Biological and medical sciences; Breast; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadherins - antagonists & inhibitors; Cadherins - genetics; Cancer; Carcinogenesis; Cell Biology; Cell differentiation; Cell Line, Transformed; Cell Line, Tumor; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Differentiation; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; E-Cadherin; Embryogenesis; Enhancer of Zeste Homolog 2 Protein; Enhancers; Epithelial cells; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Gene Silencing; Genetic aspects; Genetics; Health aspects; Histone deacetylase; Histone H3; Histones - metabolism; Human Genetics; Humans; Inhibitor drugs; Internal Medicine; Internet; Lysine; Male; Medicine; Medicine & Public Health; Methylation; Molecular and cellular biology; Neoplasm Invasiveness; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oncogenes; Oncology; original-article; Polycomb group proteins; Polycomb Repressive Complex 2; Prostate; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Repressor Proteins - genetics; Repressor Proteins - metabolism; Solid tumors; Stem cells; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor suppressor genes; Tumors; Urinary bladder; X-chromosome inactivation; United States; histone; E-cadherin; epigenetics; polycomb group protein; EZH2; Epigenetics; Repression; Malignant tumor; Histone; E Cadherin; Carcinogenesis; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.333

Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.