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ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis

Nature Medicine volume 24, pages 1887–1898 (2018)Cite this article

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Abstract

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.

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Fig. 1: OC2 is predicted to be active in mCRPC.
Fig. 2: Inverse relationship between OC2 and AR nuclear localization in radical prostatectomy specimens.
Fig. 3: OC2 suppresses the AR transcriptional program.
Fig. 4: OC2 activates a lethal transcriptional program.
Fig. 5: OC2 promotes mCRPC tumor growth and metastasis.
Fig. 6: Inhibition of OC2 with a small molecule.

Data availability

Data generated or analyzed during this study are included in this published article (and its supplementary information files). ChIP-seq and microarray data generated in this study were deposited in GEO (GSE97551, GSE97548, GSE97549). The DISC cohort data are available at www.thepcta.org.

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Acknowledgments

This study was supported by Department of Defense (DOD) grant no. W81XWH-16-1-0567 (M.R.F); NCI grant no. 1R01CA143777 (M.R.F.); NCI grant no. 1R01CA220327 (M.R.F. and S.J.F.); NIDDK grant no. 1R01DK087806 (M.R.F.); Prostate Cancer Foundation Challenge Grant grant no. 17CHAL04 (I.P.G.); Spielberg Discovery Fund in Prostate Cancer Research (B.S.K. and M.R.F.); NCI grant no. 2P01CA098912 (L.W.K.C.); Jean Perkins Foundation (I.P.G.); Movember/PCR GAP1 Unique TMAs Project (I.P.G.); DOD grant no. PC131996 (I.P.G.); DOD grant no. PC130244 (I.P.G.); NCI grant no. U54 CA143931 (I.P.G.); DOD grant no. W81XWH-14-1-0152 (S.Y.); Urology Care Foundation Research Scholar Award and Chesapeake Urology Associates Research Scholar Fund (M.R.); 2018 Donna and Jesse Garber Award for Cancer Research, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center (M.R.); Urology Care Foundation Research Scholars Program of AUA Western Section Research Scholar Fund (S.Y.). The authors are very appreciative of technical and conceptual contributions from N. Bhowmick, R. Matusik, V. Placencio, K. Kelly, M. Beshiri, W.R. Wiedemeyer, P.J. Aspuria, C. Spinelli, H. Soule, and the Biobank & Translational Research Core at Cedars-Sinai Medical Center.

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Author notes

  1. Wen-Chin Huang

    Present address: Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

  2. These authors contributed equally: Mirja Rotinen, Sungyong You.

Authors and Affiliations

  1. Division of Cancer Biology and Therapeutics, Departments of Surgery & Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Mirja Rotinen, Sungyong You, Julie Yang, Mariana Reis-Sobreiro, Wen-Chin Huang, Fangjin Huang, Kenneth Steadman, Stephen J. Freedland, Dolores Di Vizio, Beatrice S. Knudsen & Michael R. Freeman

  2. The Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Simon G. Coetzee & Dennis J. Hazelett

  3. Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Xinlei Pan & Ramachandran Murali

  4. Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Alberto Yáñez

  5. Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Chia-Yi Chu & Leland W. K. Chung

  6. Department of Urology, University of Washington, Seattle, WA, USA

    Colm M. Morrissey & Eva Corey

  7. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Peter S. Nelson

  8. Department of Urology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Isla P. Garraway

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Contributions

Conceptualization, M.R., S.Y., and M.R.F. Methodology, M.R., S.Y., and M.R.F. Investigation, M.R., S.Y., J.Y., M.R.-S., W.-C.H., X.P., A.Y., K.S., C.Y.C., L.W.K.C, and M.R.F. Software, S.Y., S.G.C, F.H., and D.J.H. Validation and formal analysis, M.R. and S.Y. Visualization, M.R., S.Y., and M.R.F. Project administration, M.R.F. Data curation, S.Y. and S.G.C. Resources, B.K., I.P.G., C.M.M., P.S.N., and E.C. Writing original draft, M.R, S.Y., and M.R.F. Writing, review, and editing, B.S.K., I.P.G., L.W.C.K., S.J.F., D.D.V., R.M., M.R, S.Y., and M.R.F. Funding acquisition, M.R., S.Y., I.P.G., B.S.K., and M.R.F. Supervision, M.R.F.

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Correspondence to Michael R. Freeman.

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Cedars-Sinai Medical Center has pending patent applications PCT/US2017/034768 (M.R.F., M.R., R.M., and S.Y.) and US62/548,879 (M.R.F., M.R., R.M., and S.Y.) relevant to this study.

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Rotinen, M., You, S., Yang, J. et al. ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med 24, 1887–1898 (2018). https://doi.org/10.1038/s41591-018-0241-1

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