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.
Cell reports. 2016 Apr 06 [Epub ahead of print]
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
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China., Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China., Department of Urology, University of Washington, Seattle, WA 98195, USA., Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Ionis Pharmaceuticals Inc., Carlsbad, CA 92010, USA., Ionis Pharmaceuticals Inc., Carlsbad, CA 92010, USA., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China., Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: ., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: .