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

A Corrigendum to this article was published on 07 June 2016

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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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Figure 1: ROR-γ overexpression is associated with mCRPC progression and is required for the survival of prostate cancer cells.
Figure 2: ROR-γ antagonists inhibit the growth of CRPC cells.
Figure 3: ROR-γ controls the AR-dependent gene programs.
Figure 4: ROR-γ inhibition strongly suppresses the expression of AR and its variants, and eliminates AR genome binding.
Figure 5: ROR-γ directly controls AR gene expression through an exonic RORE and SRCs.
Figure 6: ROR-γ antagonists potently inhibit tumor growth and metastasis.

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Change history

  • 22 April 2016

    In Figure 2a of the version of this article initially published online, one phenyl ring was inadvertently deleted from the chemical structure of compound SR2211. One affiliation of H.-W.C. (Veterans Affairs Northern California Health Care System–Mather, Mather, California, USA) was also inadvertently omitted. These errors have been corrected for the print, PDF and HTML versions of this article.

  • 07 June 2016

    Nat. Med.; doi:10.1038/nm.4070; corrected online 22 April 2016 In Figure 2a of the version of this article initially published online, one phenyl ring was inadvertently deleted from the chemical structure of compound SR2211. One affiliation of H.-W.C. (Veterans Affairs Northern California Health Care System–Mather, Mather, California, USA) was also inadvertently omitted.

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Acknowledgements

We thank D. Wu, Q. Wang, D. Chen, F. Wu, F. Li, Y. He and J. Shen for their technical expertise and for their critical comments. We thank C. Sawyers and A. van Bokhoven for providing LAPC4 and PC346C cells. This work was supported in part by grants from the Bridge Program of the University of California, Davis, Research Office (to H.-W.C.); the US National Institutes of Health (NIH) (R01CA206222 to H.-W.C.); the US Department of Veterans Affairs; the Office of Biomedical Laboratory Research and Development Service (Merit Award I01BX002237 to H.-W.C.); the 100 Talents Projects of Chinese Academy of Sciences, the National Natural Science Foundation, the Guangzhou Healthcare Collaborative Innovation Programs and the Key Basic Research Program of China (grant 81373325, grant 20150820225 and 973 program grant 2013CB910601 to Y.X.); the Howard Hughes Medical Institute; the NIH (P30CA014195, DK057978, HL088093 and HL105278 to R.M.E.) and grants from Ipsen Biomeasure and the Samuel Waxman Cancer Research Foundation (to R.M.E.); the NIH (R01CA150197 and R01CA165263 to H.-J. K.); the US Department of Defense (PC111467 to C.P.E.) and a Stand Up To Cancer—Prostate Cancer Foundation—Prostate Dream Team Translational Cancer Research Grant. This research grant is made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (SU2C-AACR-PCF DT0812 to C.P.E.) and the NIH (R01CA168601 to A.C.G.).

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H.-W.C., J.W. and J.X.Z. conceived and initiated the research. H.-W.C., J.W., Y.X., R.M.E. and H.-J.K. designed the research. J.W., J.X.Z., X.X., D.C., Y.Z., Z.D., Q.X., J.C.Y. and M.C.L. performed the experiments. H.-W.C., J.W., J.X.Z., J.X., Y.X., M.C.L. and A.D.B. analyzed the data. H.-W.C., J.W., Y.X., A.C.G., C.P.E., K.S.L., H.J.K. and R.M.E. wrote and/or edited the manuscript.

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Correspondence to Yong Xu or Hong-Wu Chen.

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H.W.C., J.X.Z., J.W. and Y.X. are co-inventors of a patent application covering methods of treating cancer with ROR-γ inhibitors. The other authors declare no competing financial interests.

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Wang, J., Zou, J., Xue, X. et al. ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Nat Med 22, 488–496 (2016). https://doi.org/10.1038/nm.4070

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