Abstract 1497: A PRC2 independent role of EZH2 in androgen receptor signaling in prostate cancer

Prostate cancer is the most frequently diagnosed cancer and third most frequent cause of cancer deaths in US males. Prostate cancer patients have benefitted from androgen deprivation therapy and small molecular inhibitors targeting androgen receptor (AR). However, 30% of patients have primary resistance to both forms of treatment with a majority of patients eventually developing resistance to these therapies and progressing from androgen dependent prostate cancer (ADPC) to castration resistant prostate cancer (CRPC). Unfortunately, there are no effective therapeutic options available for CRPC patients, so novel and more effective therapeutic strategies for CRPC are urgently needed. Enhancer of Zeste 2 (EZH2) is a well-characterized oncogene that is one of the most highly upregulated genes in aggressive PCa and suggested as a prognostic biomarker. EZH2 is a part of polycomb repressive complex2 (PRC2) with embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12) to function as a repressor through the SET domain, especially Histidine 689 to methylate H3K27. Recently, some studies suggest a context-dependent or PRC2 independent function of EZH2, but new functional role of EZH2 in cancer that are yet to be delineated. In the present study, we demonstrated EZH2 enhances AR signaling through direct AR promoter occupancy at exon1, independent of histone methyltransferase activity. EZH2 has a dual role as a transcriptional activator mediated by AR and an epigenetic silencer mediated by H3K27me3. Therefore, simultaneously targeting EZH2 and AR by drug inhibitors, EPZ and enzalutamide (Enz), respectively, leads to synergistic cell growth inhibition. Taken together, our data reveal a dual function of EZH2 in PCa as a transcriptional activator and an epigenetic silencer. We believe that this study provide not only a novel function of EZH2 in the regulating AR signaling pathway but also provide novel therapeutic strategies for advanced prostate cancer which currently has no therapeutic options available. Citation Format: Yongik Lee, Jung a Kim, Zhao Changsheng, Xiadong Lu, Ka Wing Fong, Jindan Yu. A PRC2 independent role of EZH2 in androgen receptor signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1497.