Abstract 4799: Epigenetic antagonism between Polycomb and SWI/SNF complexes during oncogenic transformation

Abstract

Abstract Epigenetic alterations serve critical roles in cell fate decisions and have increasingly been implicated in cancer formation. The Polycomb Group (PcG) protein EZH2 mediates epigenetic gene silencing, displays pro-oncogenic properties in cell lines and is frequently overexpressed in cancer. Conversely, loss of function mutations in the tumor suppressor gene SNF5, a core subunit of the SWI/SNF chromatin remodeling complex, occur in several types of aggressive human cancers. Intriguingly, analysis of homeotic mutants in Drosophila suggests that PcG and SWI/SNF can serve antagonistic roles in the epigenetic control of gene expression. Here we have investigated functional relationships between these epigenetic regulators in oncogenic transformation by examining the role of EZH2 in tumors driven by SNF5 loss. Notably, SNF5-mutant tumors, despite being highly aggressive, are diploid and genomically stable, making them an ideal model with which to elucidate epigenetic drivers of oncogenesis. We show that targeted inactivation of Snf5 leads to increased expression of Ezh2 and that EZH2 is upregulated in SNF5- deficient cancers. A key mechanism by which SNF5 loss promotes oncogenesis is via downregulation of the p16INK4a tumor suppressor. We show that inactivation of Ezh2 restores normal levels of p16INK4a to Snf5-deficient fibroblasts. We further show that reducing the levels of EZH2 in a human SNF5-deficient tumor cell line leads to increased levels of p16INK4a accompanied by slowed proliferation and cellular senescence. Most importantly, using conditional mouse models, we show that inactivation of EZH2 completely blocks tumor formation driven by SNF5 loss. Our results demonstrate an essential role for Ezh2 in oncogenic transformation in vivo and show that perturbing the epigenetic balance of gene expression mediated by EZH2 silencing and SWI/SNF activation can have a profound effect on tumor formation. Further, we establish that targeted inhibition of EZH2 in vivo can have potent anti-cancer effects. 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 4799.