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BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer

Oncogene volume 38, pages 5658–5669 (2019)Cite this article

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Abstract

BET bromodomain inhibitors block prostate cancer cell growth at least in part through c-Myc and androgen receptor (AR) suppression. However, little is known about other transcriptional regulators whose suppression contributes to BET bromodomain inhibitor anti-tumor activity. Moreover, the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency is increasing, is also unknown. Herein, we demonstrate that BET bromodomain inhibition blocks growth of a diverse set of CRPC cell models, including those that are AR-independent or in which c-Myc is not suppressed. To identify transcriptional regulators whose suppression accounts for these effects, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1 and then performed RNA-sequencing followed by Master Regulator computational analysis. This approach identified several previously unappreciated transcriptional regulators that are highly expressed in CRPC and whose suppression, via both transcriptional or post-translational mechanisms, contributes to the anti-tumor activity of BET bromodomain inhibitors.

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Acknowledgements

This research was supported by: National Institutes of Health (NIH)/National Cancer Institute (NCI) R01 award CA178610; the Pacific Northwest Prostate Cancer SPORE/NCI (P50 CA097186); Cancer Center Support Grant (CCSG) (P30 CA069533); the Oregon Clinical and Translational Research Institute (OCTRI) (UL1TR000128) from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH; Department of Defense Synergistic Idea Award (W81XWH-13-1-0420); Department of Defense Impact Awards (W81XWH-16-1-0597 and W81XWH-16-1-1601). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or DOD. Other support includes: Wayne D. Kuni and Joan E. Kuni Foundation, Prospect Creek Foundation, a Hope Foundation Award, and a Stand Up to Cancer—Prostate Cancer Foundation—Prostate Dream Team Translational Cancer Research Grant (SU2C-AACR-DT0409); 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 (7465sc). We thank Dr. James Bradner at Dana-Farber Cancer Institute for providing the JQ1 compound used in in vivo studies.

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  1. Deceased: Junior Tayou

Authors and Affiliations

  1. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA

    Daniel J. Coleman, Lina Gao, Carly J. King, Jacob Schwartzman, Joshua Urrutia, Archana Sehrawat, Junior Tayou, Kami E. Chiotti, Daniel S. Derrick, Laura M. Heiser & Joshi J. Alumkal

  2. Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA

    Carly J. King, Daniel S. Derrick, Duanchen Sun, Zheng Xia & Laura M. Heiser

  3. Computational Biology Program, Oregon Health & Science University, Portland, OR, 97239, USA

    Ariel Balter & Julja Burchard

  4. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA

    Kami E. Chiotti & Joshi J. Alumkal

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Contributions

DJC, LG, JS, LMH, and JJA designed the research; DJC, LG, JS, JU, AS, and JT performed the experiments; DJC, LG, CJK, JS, AB, JB, KEC, DSD, DS, ZX, LMH, and JJA analyzed the data, DJC, LG, CJK, JS, AB, LMH, and JJA provided critical analysis of the manuscript; DJC and JJA wrote the paper.

Corresponding authors

Correspondence to Laura M. Heiser or Joshi J. Alumkal.

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Conflict of interest

JJA has performed consulting or held an advisory role with Astellas Pharma, Bayer, and Janssen Biotech, Inc. OHSU has received institutional research funding from Aragon Pharmaceuticals Inc., Astellas Pharma, Norvartis, Zenith Epigenetics Ltd, and Gilead Sciences Inc. These interests had no role in the design or conduct of this study. The remaining authors declare that they have no conflict of interest.

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Coleman, D.J., Gao, L., King, C.J. et al. BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer. Oncogene 38, 5658–5669 (2019). https://doi.org/10.1038/s41388-019-0815-5

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