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ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer
Nature Medicine (2016)
  • Jujian Wang, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis
  • June X. Zou, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis
  • Xiaoqian Xue, Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
  • Demin Cai, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis
  • Yan Zhang, Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
  • Zguhuab Duan, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis
  • Qiuping Xiang, Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
  • Joy C. Yang, Department of Urology, School of Medicine, University of California, Davis
  • Maggie C Louie, Department of Natural Sciences and Mathematics, Dominican University of California
  • Alexander D Borowsky, Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis
  • Allen C Gao, Department of Urology, School of Medicine, University of California, Davis
  • Christopher P. Evans, Department of Urology, School of Medicine, University of California, Davis
  • Kit S. Lam, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis
  • Jianzhen Xu, Shantou University Medical College
  • Hsing-Jien Kung, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis
  • Ronald M. Evans, Department of Urology, School of Medicine, University of California, Davis
  • Yong Xu, nstitute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
  • Hong-Wu Chen, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis
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.
Keywords
  • Cancer,
  • castration-resistant prostate cancer
Publication Date
May, 2016
Citation Information
Jujian Wang, June X. Zou, Xiaoqian Xue, Demin Cai, et al.. "ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer" Nature Medicine Vol. 22 Iss. 5 (2016) p. 488 - 496 ISSN: 1078-8956
Available at: http://works.bepress.com/maggie_louie/30/