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.
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Liguo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Shancheng
authors.initials: S
authors.lastname: Ren
authors.affiliation: 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.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Blackburn
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Melissa S
authors.initials: MS
authors.lastname: McNulty
authors.affiliation: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Qiao
authors.affiliation: Department of Urology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Kohli
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, CA 92010, USA.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, CA 92010, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: MacLeod
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ekker
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
authors.affiliation: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: sunyhsmmu@126.com.
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 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: huang.haojie@mayo.edu.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056906:Cyclin T / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006801:Humans; D008297:Male; D008954:Models, Biological; D059372:Nucleotide Motifs / Q000235:genetics; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D012313:RNA / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C410798:AR protein, human; D056906:Cyclin T; D011944:Receptors, Androgen; D012694:Serine; D012313:RNA; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II; D017430:Prostate-Specific Antigen