Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer

Yu Zhao, Liguo Wang, Shancheng Ren, Lan Wang, Patrick R. Blackburn, Melissa S. McNulty, Xu Gao, Meng Qiao, Robert L. Vessella, Manish Kohli, Jun Zhang, R. Jeffrey Karnes, Donald J. Tindall, Youngsoo Kim, Robert MacLeod, Stephen C. Ekker, Tiebang Kang, Yinghao Sun, Haojie Huang

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

Original languageEnglish (US)
Pages (from-to)599-610
Number of pages12
JournalCell reports
Volume15
Issue number3
DOIs
StatePublished - Apr 19 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhao, Y., Wang, L., Ren, S., Wang, L., Blackburn, P. R., McNulty, M. S., Gao, X., Qiao, M., Vessella, R. L., Kohli, M., Zhang, J., Karnes, R. J., Tindall, D. J., Kim, Y., MacLeod, R., Ekker, S. C., Kang, T., Sun, Y., & Huang, H. (2016). Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer. Cell reports, 15(3), 599-610. https://doi.org/10.1016/j.celrep.2016.03.038