Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer

• Published in: International journal of cancer 2019-07, Vol.145 (2), p.415-426
• Main Authors: Liu, Qipeng, Wang, Guangyu, Li, Qiaqia, Jiang, Weihua, Kim, Jung‐Sun, Wang, Rui, Zhu, Sen, Wang, Xiaoju, Yan, Lin, Yi, Yang, Zhang, Lili, Meng, Qingshu, Li, Chao, Zhao, Dongyu, Qiao, Yuanyuan, Li, Yong, Gursel, Demirkan B., Chinnaiyan, Arul M., Chen, Kaifu, Cao, Qi
• Format: Article
• Language: English
• Subjects: androgen receptor; Androgen receptors; Androgens; astemizole; Cancer; Cell proliferation; Cell self-renewal; Ectoderm; EED; Embryogenesis; EZH2; Homology; Medical research; Metastases; Polycomb group proteins; Prostate cancer; Proteins; Stem cells
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32118

Polycomb group proteins are important epigenetic regulators for cell proliferation and differentiation, organ development, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including Enhancer of zeste homolog 2 (EZH2), promote proliferation, migration, invasion and metastasis of cancer cells, as well as self‐renewal of cancer stem cells. In our study, we report that EZH2 and embryonic ectoderm development (EED) indicate respective direct interaction with androgen receptor (AR). In the context of AR‐positive prostate cancer, EZH2 and EED regulate AR expression levels and AR downstream targets. More importantly, we demonstrate that targeting EZH2 with the small‐molecule inhibitor astemizole in cancer significantly represses the EZH2 and AR expression as well as the neoplastic capacities. These results collectively suggest that pharmacologically targeting EZH2 might be a promising strategy for advanced prostate cancer. What's new? Polycomb group proteins are epigenetic regulators with important roles in cancer initiation and progression. Among them, EZH2 is a downstream target of androgen receptor (AR) in prostate cancer. How EZH2 regulates AR functions in castration‐resistant prostate cancer (CRPC) however remains unclear. This study reveals that EZH2 and EED‐‐the two core catalytic subunits of the PRC2 class of Polycomb group proteins‐‐play a critical role related to the AR pathway in prostate cancer. Moreover, astemizole was a potent PRC2 disruptor that significantly represses EZH2 and AR expression in prostate cancer cells, thus representing a potential medication for castration‐resistant prostate cancer.