Abstract LB-237: Epigenetic antagonism between Polycomb and SWI/SNF complexes duringoncogenic transformation

Abstract While epigenetic alterations are widely present in cancers, in the context of genomic instability it has been difficult to determine the degree to which epigenetic alterations serve as primary drivers of tumorigenesis. Cancers initiated by mutation of the SNF5 chromatin remodeling subunit, despite being highly aggressive and lethal, are diploid and genomically stable, making them an ideal model for this purpose. SNF5 is a core subunit of the SWI/SNF chromatin complex and is mutated in the large majority of malignant rhabdoid tumors (MRT), highly lethal cancers that occur in kidney, brain, and soft tissues of young children. Inactivating mutations in SNF5 have also recently been found to occur in a variety of other cancers and mutations in other SWI/SNF subunits occur frequently in ovarian, endometrial, renal, and lung cancers. Given our findings of genomic stability, we hypothesize that the consequences of SNF5 loss are fundamentally epigenetic in nature; that characterization of the epigenetic changes present in our model systems, rather than in cancers with genome instability, will identify those epigenetic alterations capable of driving oncogenic transformation; and lastly that cancers carrying mutations in the SWI/SNF complex can be effectively treated with epigenetically targeted therapies. Analysis of Drosophila mutants suggests that Polycomb and SWI/SNF complexes can serve antagonistic developmental roles. However, the relevance of this relationship to human disease is unclear. Here we have investigated functional relationships between these epigenetic regulators in oncogenic transformation. Mechanistically, we show that loss of the SNF5 tumor suppressor leads to elevated expression of the Polycomb gene EZH2 and that Polycomb targets are broadly H3K27-trimethylated and repressed in SNF5-deficient fibroblasts and cancers. Further, we show antagonism between SNF5 and EZH2 in the regulation of stem cell-associated programs and that Snf5 loss activates those programs. Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss. Collectively, we demonstrate that the rapid onset of tumor formation following SNF5 loss arises due to imbalanced epigenetic antagonism between the SWI/SNF complex and the Polycomb complex PRC2. Our work reveals essential roles for epigenetic modifications during tumor formation and demonstrates that inactivation of EZH2 can have therapeutic efficacy against cancer in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-237. doi:10.1158/1538-7445.AM2011-LB-237