title: Mechanisms of the androgen receptor splicing in prostate cancer cells.
abstract: Prostate tumors develop resistance to androgen deprivation therapy (ADT) by multiple mechanisms, one of which is to express constitutively active androgen receptor (AR) splice variants lacking the ligand-binding domain. AR splice variant 7 (AR-V7, also termed AR3) is the most abundantly expressed variant that drives prostate tumor progression under ADT conditions. However, the molecular mechanism by which AR-V7 is generated remains unclear. In this manuscript, we demonstrated that RNA splicing of AR-V7 in response to ADT was closely associated with AR gene transcription initiation and elongation rates. Enhanced AR gene transcription by ADT provides a prerequisite condition that further increases the interactions between AR pre-mRNA and splicing factors. Under ADT conditions, recruitment of several RNA splicing factors to the 3' splicing site for AR-V7 was increased. We identified two RNA splicing enhancers and their binding proteins (U2AF65 and ASF/SF2) that had critical roles in splicing AR pre-mRNA into AR-V7. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-V7 levels in prostate cancer cells.
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: L L
authors.initials: LL
authors.lastname: Liu
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Xie
authors.affiliation: Department of Medicine, University of Washington School of Medicine and VAPSHCS-GRECC, Seattle, WA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Medicine, University of Washington School of Medicine and VAPSHCS-GRECC, Seattle, WA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Plymate
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mostaghel
authors.affiliation: 1] Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada [2] Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Dong
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen