title: MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators.
abstract: Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of miR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression.
authors.affiliation: Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Emeli M
authors.initials: EM
authors.lastname: Nilsson
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Kristian B
authors.initials: KB
authors.lastname: Laursen
authors.affiliation: Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom.|School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Whitchurch
authors.affiliation: Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: McWilliam
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Ødum
authors.affiliation: Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Persson
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Heery
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
authors.affiliation: Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom.|Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
mesh_terms: D000728:Androgens / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D063185:Epigenetic Repression; D004847:Epithelial Cells / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D056466:Histone Demethylases; C495195:KDM1A protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Gleason; epigenetic; metastases; nuclear receptor; prostate