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

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)488-496
Number of pages9
JournalNature Medicine
Volume22
Issue number5
DOIs
Publication statusPublished - May 1 2016
Externally publishedYes

Fingerprint

Castration
Androgen Receptors
Prostatic Neoplasms
Tumors
Therapeutics
Genes
Nuclear Receptor Coactivator 3
Neoplasms
Nuclear Receptor Coactivator 1
Retinoic Acid Receptors
Gene Regulatory Networks
Response Elements
Transcription
Tumor Cell Line
Heterografts
Toxicity
Cells
Genome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. / Wang, Junjian; Zou, June X.; Xue, Xiaoqian; Cai, Demin; Zhang, Yan; Duan, Zhijian; Xiang, Qiuping; Yang, Joy C.; Louie, Maggie C.; Borowsky, Alexander D.; Gao, Allen C.; Evans, Christopher P.; Lam, Kit S.; Xu, Jianzhen; Kung, Hsing Jien; Evans, Ronald M.; Xu, Yong; Chen, Hong Wu.

In: Nature Medicine, Vol. 22, No. 5, 01.05.2016, p. 488-496.

Research output: Contribution to journalArticle

Wang, J, Zou, JX, Xue, X, Cai, D, Zhang, Y, Duan, Z, Xiang, Q, Yang, JC, Louie, MC, Borowsky, AD, Gao, AC, Evans, CP, Lam, KS, Xu, J, Kung, HJ, Evans, RM, Xu, Y & Chen, HW 2016, 'ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer', Nature Medicine, vol. 22, no. 5, pp. 488-496. https://doi.org/10.1038/nm.4070
Wang, Junjian ; Zou, June X. ; Xue, Xiaoqian ; Cai, Demin ; Zhang, Yan ; Duan, Zhijian ; Xiang, Qiuping ; Yang, Joy C. ; Louie, Maggie C. ; Borowsky, Alexander D. ; Gao, Allen C. ; Evans, Christopher P. ; Lam, Kit S. ; Xu, Jianzhen ; Kung, Hsing Jien ; Evans, Ronald M. ; Xu, Yong ; Chen, Hong Wu. / ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. In: Nature Medicine. 2016 ; Vol. 22, No. 5. pp. 488-496.
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