@article{6cb63cc0c4cd4e249d5cc9d115d52409,
title = "Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer",
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.",
author = "Yu Zhao and Liguo Wang and Shancheng Ren and Lan Wang and Blackburn, {Patrick R.} and McNulty, {Melissa S.} and Xu Gao and Meng Qiao and Vessella, {Robert L.} and Manish Kohli and Jun Zhang and Karnes, {R. Jeffrey} and Tindall, {Donald J.} and Youngsoo Kim and Robert MacLeod and Ekker, {Stephen C.} and Tiebang Kang and Yinghao Sun and Haojie Huang",
note = "Funding Information: This work was supported, in part, by grants from the NIH (CA134514, CA130908, and CA193239) and the DOD (W81XWH-09-1-622 and W81XWH-14-1-0486), a 2015 Movember Foundation-Prostate Cancer Foundation Challenge Award (2015CHAL518), the Mayo Clinic Center for Individualized Medicine Pilot Award, and the Mayo Clinic Center for Biomedical Discovery Platform Grant (to H.H.); the T.J. Martell Foundation (to D.J.T. and H.H.); the Program for Changjiang Scholars (No. IRT1111), the National Basic Research Program of China (2012CB518300), and the National Natural Science Foundation of China (81430058) (to Y.S.); the National Natural Science Foundation of China (81472397), Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator (XYQ2013077), and Shanghai Municipal Education Commission (to S.R.); and grants from the NIH (GM63904 and P30 DK84567) (to S.C.E.). Funding Information: This work was supported, in part, by grants from the NIH ( CA134514 , CA130908 , and CA193239 ) and the DOD ( W81XWH-09-1-622 and W81XWH-14-1-0486 ), a 2015 Movember Foundation - Prostate Cancer Foundation Challenge Award ( 2015CHAL518 ), the Mayo Clinic Center for Individualized Medicine Pilot Award, and the Mayo Clinic Center for Biomedical Discovery Platform Grant (to H.H.); the T.J. Martell Foundation (to D.J.T. and H.H.); the Program for Changjiang Scholars (No. IRT1111 ), the National Basic Research Program of China ( 2012CB518300 ), and the National Natural Science Foundation of China ( 81430058 ) (to Y.S.); the National Natural Science Foundation of China ( 81472397 ), Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator ( XYQ2013077 ), and Shanghai Municipal Education Commission (to S.R.); and grants from the NIH ( GM63904 and P30 DK84567 ) (to S.C.E.). Publisher Copyright: {\textcopyright} 2016 The Authors.",
year = "2016",
month = apr,
day = "19",
doi = "10.1016/j.celrep.2016.03.038",
language = "English (US)",
volume = "15",
pages = "599--610",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}