Polycomb Protein Ezh2 Activates Wnt/Beta-Catenin Signaling To Promote Hepatocellular Carcinoma Development

Aberrant activation of the canonical Wnt pathway due to accumulation of β-catenin occurs in approximately 70% of hepatocellular carcinomas (HCCs) and contributes to their initiation, development and progression. Genetic mutations in the components of this pathway account for only a subset of HCCs with β-catenin accumulation, suggesting that an alternative mechanism for Wnt/β-catenin activation is prevailing. Enhancer of zeste homolog 2 (EZH2) is known to promote tumorigenesis by down-regulating tumor-suppressor genes; however, whether EZH2 regulates oncogenic pathways is unclear. Using chromatin immunoprecipitation microarray, we uncovered 12 Wnt/β-catenin signal antagonists whose promoters were concordantly occupied by EZH2 and repressive histone modifications in hepatocellular HCC cells. EZH2 over-expressed in 42% (75/179) of human HCCs and significantly associated with β-catenin accumulation. Concomitant inhibition of EZH2 and histone deacetylase transcriptionally activated Wnt/β-catenin signal antagonists, suppressed T-cell factor-dependent transcriptional activity and down-regulated β-catenin transcriptional targets in HCC cells. Conversely, ectopic EZH2 over-expression in nontumorigenic hepatocytes increased cellular proliferation in a β-catenin-dependent manner and promoted tumorigenicity. This study uncovers an EZH2-mediated epigenetic mechanism that leads to Wnt/β-catenin signaling dyregulation in human HCC and suggests that therapeutic interventions targeting EZH2 may confer a clinical benefit in β-catenin-driven malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4881.