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

Daniel J. Coleman, Lina Gao, Carly J. King, Jacob Schwartzman, Joshua Urrutia, Archana Sehrawat, Junior Tayou, Ariel Balter, Julja Burchard, Kami E. Chiotti, Daniel S. Derrick, Duanchen Sun, Zheng Xia, Laura M. Heiser, Joshi J. Alumkal

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5658-5669
Number of pages12
JournalOncogene
Volume38
Issue number28
DOIs
StatePublished - Jul 11 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Coleman, D. J., Gao, L., King, C. J., Schwartzman, J., Urrutia, J., Sehrawat, A., Tayou, J., Balter, A., Burchard, J., Chiotti, K. E., Derrick, D. S., Sun, D., Xia, Z., Heiser, L. M., & Alumkal, J. J. (2019). BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer. Oncogene, 38(28), 5658-5669. https://doi.org/10.1038/s41388-019-0815-5