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

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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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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