title: Putative Prostate Cancer Risk SNP in an Androgen Receptor-Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites.
abstract: Genome-wide association studies have identified genomic loci, whose single-nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin-immunoprecipitation-coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor-binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH) was within a novel putative auxiliary AR-binding motif, which is enriched in the neighborhood of canonical androgen-responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of MLPH in primary prostate tumors was significantly lower in those with the G compared with the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favorable PCa risk profile points out a tumor-suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH.
authors.affiliation: Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria.|Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria.
authors.forename: Huajie
authors.initials: H
authors.lastname: Bu
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.affiliation: Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria.|Oncotyrol, Center for Personalized Cancer Medicine, Innsbruck, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schlick
authors.affiliation: Biocenter Innsbruck, Section for Molecular Pathophysiology, Medical University of Innsbruck, Innsbruck, Austria.|Center for Biomedicine, EURAC Research, Bolzano, Italy.
authors.forename: Johannes
authors.initials: J
authors.lastname: Rainer
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.|Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Manke
authors.affiliation: Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria.|Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.affiliation: Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pasqualini
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Chines
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.|Cologne Center for Genomics, University of Cologne, Germany.
authors.forename: Michal R
authors.initials: MR
authors.lastname: Schweiger
authors.affiliation: Center for Biomedicine, EURAC Research, Bolzano, Italy.|Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Christian
authors.initials: C
authors.lastname: Fuchsberger
authors.affiliation: Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D059372:Nucleotide Motifs; D020641:Polymorphism, Single Nucleotide; D056510:Position-Specific Scoring Matrices; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*; D020218:Response Elements; D047368:Tumor Burden
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C492410:MLPH protein, human; D011944:Receptors, Androgen
keywords: AR; MLPH; androgen receptor; androgen regulation; melanophilin; prostate cancer; risk SNPs