title: miR-22 and miR-29a Are Members of the Androgen Receptor Cistrome Modulating LAMC1 and Mcl-1 in Prostate Cancer.
abstract: The normal prostate as well as early stages and advanced prostate cancer (PCa) require a functional androgen receptor (AR) for growth and survival. The recent discovery of microRNAs (miRNAs) as novel effector molecules of AR disclosed the existence of an intricate network between AR, miRNAs and downstream target genes. In this study DUCaP cells, characterized by high content of wild-type AR and robust AR transcriptional activity, were chosen as the main experimental model. By integrative analysis of chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray expression profiling data, miRNAs putatively bound and significantly regulated by AR were identified. A direct AR regulation of miR-22, miR-29a, and miR-17-92 cluster along with their host genes was confirmed. Interestingly, endogenous levels of miR-22 and miR-29a were found to be reduced in PCa cells expressing AR. In primary tumor samples, miR-22 and miR-29a were less abundant in the cancerous tissue compared with the benign counterpart. This specific expression pattern was associated with a differential DNA methylation of the genomic AR binding sites. The identification of laminin gamma 1 (LAMC1) and myeloid cell leukemia 1 (MCL1) as direct targets of miR-22 and miR-29a, respectively, suggested a tumor-suppressive role of these miRNAs. Indeed, transfection of miRNA mimics in PCa cells induced apoptosis and diminished cell migration and viability. Collectively, these data provide additional information regarding the complex regulatory machinery that guides miRNAs activity in PCa, highlighting an important contribution of miRNAs in the AR signaling.
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pasqualini
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Huajie
authors.initials: H
authors.lastname: Bu
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Martin
authors.initials: M
authors.lastname: Puhr
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Johannes
authors.initials: J
authors.lastname: Rainer
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schlick
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Angelova
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Trajanoski
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Börno
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Michal R
authors.initials: MR
authors.lastname: Schweiger
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Christian
authors.initials: C
authors.lastname: Fuchsberger
authors.affiliation: Department of Urology (L.P., H.B., M.P., B.S., G.S., H.K.), Division of Experimental Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Research Institute for Biomedical Aging Research (H.B.), University of Innsbruck, 6020 Innsbruck, Austria; Medical Genomics and Metabolic Genetics Branch (N.N.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Biocenter Innsbruck (J.R.), Section for Molecular Pathophysiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Center for Biomedicine (J.R., C.F.), EURAC Bolzano, 39100 Bolzano, Italy; Oncotyrol (B.S.), Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria; Department of Pathology (G.S.), Medical University of Innsbruck, 6020 Innsbruck, Austria; Biocenter Innsbruck (M.A., Z.T.), Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Max Planck Institute for Molecular Genetics (S.T.B., M.R.S.), 14195 Berlin, Germany; Cologne Center for Genomics (M.R.S.), University of Cologne, 50931 Cologne, Germany; and Department of Biostatistic (C.F.), University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
mesh_terms: D000728:Androgens / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016678:Genome; D006801:Humans; D007797:Laminin / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C410798:AR protein, human; D000728:Androgens; D007797:Laminin; C579095:MCL1 protein, human; C548375:MIRN22 microRNA, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011944:Receptors, Androgen; C089141:laminin gamma 1