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

Publication date: Available online 7 April 2016
Source:Cell Reports
Author(s): 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
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.

Graphical abstract

Teaser

Zhao et al. show that a group of AR-regulated eRNAs, including the PSA eRNA, are upregulated in CRPC cells in culture as well as in patient specimens. The PSA eRNA binds to CYCLIN T1, activates P-TEFb, and increases Pol II-Ser2p and cell growth, and this effect is mediated through a TAR-L motif.


from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/1qc9n0E
via IFTTT