Abstract B30: Targeting EZH2 methyltransferase activity: A novel therapeutic approach to ARID1A-deficient cancer

Abstract

Abstract Loss of function mutation of the epigenetic modulator ARID1A, a component of SWI/SNF chromatin remodeling complex, occurs in a number of cancers most notably ovarian. ARID1A is mutated in up to 60% and 30% of clear cell and endometrioid ovarian cancers, respectively. However, there currently is no effective therapy that targets ARID1A-deficient human cancers. Here we show ARID1A-deficient ovarian cancer cells are selectively sensitive to inhibition of EZH2's methyltransferase activity. EZH2 is the catalytic subunit of the polycomb repressor complex 2, which represses gene expression by generating tri-methylation epigenetic mark on lysine 27 of histone H3 (H3K27Me3). Utilizing a library of small molecules against epigenetic targets, we identified an EZH2 small molecule inhibitor that selectively inhibited the growth of ARID1A-deficient ovarian cancer cells, while exhibiting no effects in ARID1A wild-type cells. Genome-wide gene expression profile revealed that there is significant overlap of genes altered by ARID1A restoration and EZH2 methyltransferase inhibition. Specifically, the tumor suppressor and inhibitor of PI3K/AKT signaling, PIK3IP1, is regulated by both ARID1A and EZH2. Chromatin immunoprecipitation assays confirmed the occupancy of ARID1A and EZH2 at the PIK3IP1 promoter. In an intraperitoneal (IP) xenograft mouse model, EZH2 inhibitor GSK126 treatment resulted in a significant decrease in the number of IP tumor nodules. Moreover, in an independent orthotopic intra-bursal xenograft model using ARID1A wildtype and deficient cells, the EZH2 inhibitor GSK126 only suppressed the growth of ARID1A-deficient tumors. Notably, the observed effects correlated with a decrease in expression of H3K27Me3, pAKT and Ki67, a cell proliferation marker, and an increase in PIK3IP1. These data indicate loss of ARID1A and gain of EZH2 could act in epigenetic concert to promote cancer phenotypes. Taken together, these findings imply that inhibition of the methyltransferase EZH2 represents a novel therapeutic strategy for ARID1A-deficient cancers. Citation Format: Benjamin Bitler, Azat Garipov, Ie Ming Shih, Rugang Zhang. Targeting EZH2 methyltransferase activity: A novel therapeutic approach to ARID1A-deficient cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B30.