Abstract 5142: Probing the molecular mechanism of EZH2 in rhabdoid tumors

Abstract

Abstract Proteins that regulate chromatin dynamics and post-translational modifications of histones are crucial transcriptional regulators, and are implicated in diverse cellular processes including proliferation, differentiation and genome integrity control. The Polycomb repressive complex 2 (PRC2) plays a key role in the maintenance of transcriptional repression of genes necessary for normal embryonic development. Enhancer of Zeste homolog 2 (EZH2) is the catalytic subunit of PRC2 and methylates lysine 27 on histone 3 (H3K27).Overexpression and mutations of EZH2 have been reported to promote tumorigenesis [1,2]. Malignant Rhabdoid Tumors (MRTs) are highly aggressive tumors of soft tissues showing high sensitivity to an EZH2 inhibitor [1,3,4].Treatment with a highly selective and potent EZH2 inhibitor (EI1) leads to induction of p16 expression, sustained growth arrest and senescence in G401, a MRT cell line model (Fig. 1) (3, 4). Taking advantage of the strong anti-proliferative effect of EI1 in G401, we performed an shRNA screen to identify molecular targets that will confer resistance to EI1-mediated growth arrest. We hypothesized that such targets will provide novel insight of EZH2 biology in rhabdoid cancers, and may be relevant to potential mechanisms of resistance. Citation Format: Michelle Lira, Ho Man Chan, Veronica Gibaja. Probing the molecular mechanism of EZH2 in rhabdoid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5142. doi:10.1158/1538-7445.AM2014-5142