ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Junjian Wang, June X. Zou, Xiaoqian Xue, Demin Cai, Yan Zhang, Zhijian Duan, Qiuping Xiang, Joy C. Yang, Maggie C. Louie, Alexander D. Borowsky, Allen C. Gao, Christopher P. Evans, Kit S. Lam, Jianzhen Xu, Hsing Jien Kung, Ronald M. Evans, Yong Xu, Hong Wu Chen

研究成果: 雜誌貢獻文章

69 引文 斯高帕斯(Scopus)

摘要

The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.
原文英語
頁(從 - 到)488-496
頁數9
期刊Nature Medicine
22
發行號5
DOIs
出版狀態已發佈 - 五月 1 2016
對外發佈Yes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wang, J., Zou, J. X., Xue, X., Cai, D., Zhang, Y., Duan, Z., Xiang, Q., Yang, J. C., Louie, M. C., Borowsky, A. D., Gao, A. C., Evans, C. P., Lam, K. S., Xu, J., Kung, H. J., Evans, R. M., Xu, Y., & Chen, H. W. (2016). ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Nature Medicine, 22(5), 488-496. https://doi.org/10.1038/nm.4070