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

  • Nat Med. 2016 May;22(5):488-96. doi: 10.1038/nm.4070.
Junjian Wang  1 ,  June X Zou  1 ,  Xiaoqian Xue  2 ,  Demin Cai  1 ,  Yan Zhang  2 ,  Zhijian Duan  1 ,  Qiuping Xiang  2 ,  Joy C Yang  3 ,  Maggie C Louie  4 ,  Alexander D Borowsky  5 ,  Allen C Gao  3  6 ,  Christopher P Evans  3  6 ,  Kit S Lam  1  6 ,  Jianzhen Xu  7 ,  Hsing-Jien Kung  1  6 ,  Ronald M Evans  8 ,  Yong Xu  2 ,  Hong-Wu Chen  1  6  9
Affiliations
  • 1. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
  • 2. Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 3. Department of Urology, School of Medicine, University of California, Davis, Sacramento, California, USA.
  • 4. Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California, USA.
  • 5. Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
  • 6. Comprehensive Cancer Center, University of California, Davis, Sacramento, California, USA.
  • 7. Shantou University Medical College, Shantou, China.
  • 8. Gene Expression Laboratory, Salk Institute, Howard Hughes Medical Institute, Salk Institute, La Jolla, California, USA.
  • 9. Veterans Affairs Northern California Health Care System-Mather, Mather, California, USA.
PMID: 27019329 DOI: 10.1038/nm.4070
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.

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