Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator

Abstract

Summary: Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively. Last, we demonstrate enhanced efficacy of enzymatic EZH2 inhibitors when used in combination with AR antagonists in blocking the dual roles of EZH2 and suppressing prostate cancer progression in vitro and in vivo. Taken together, our study reports EZH2 as a transcriptional activator, a key target of which is AR, and suggests a drug-combinatory approach to treat advanced prostate cancer. : Kim et al. report EZH2 as a transcriptional activator that directly induces AR gene expression in a Polycomb- and methylation-independent manner, providing a mechanism to escape enzymatic EZH2 inhibitors. Combination of inhibitors with AR-targeted therapies showed a strong synergy in blocking the EZH2 downstream pathways and suppressing prostate cancer progression. Keywords: epigenetic silencing, transcription activator, androgen receptor inhibitor, enzymatic EZH2 inhibitor, GSK126, EPZ-6438, AR antagonist enzalutamide, ChIP-seq