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. Issue 1 (19th October 2015)

• Record Type: Journal Article
• Authors: Bu, Huajie; Narisu, Narisu; Schlick, Bettina; Rainer, Johannes; Manke, Thomas; Schäfer, Georg; Pasqualini, Lorenza; Chines, Peter; Schweiger, Michal R.; Fuchsberger, Christian; Klocker, Helmut
• Is Part Of: Human mutation. Volume 37:Issue 1(2016)
• Page Start: 52
• Page End: 64
• Publication Date: 2015-10-19
• Subjects: prostate cancer -- risk SNPs -- androgen receptor -- melanophilin -- MLPH -- androgen regulation -- AR; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22909
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : 1490 primary androgen receptor (AR) target genes were identified in DuCaP prostate cancer cells. Prostate cancer risk SNPs and linked SNPs are significantly enriched in genomic AR target sites. A putative risk SNP in an AR binding site of the MLPH gene regulates melanophilin expression. More favorable tumor risk profile in prostate cancer patients with higher melanophilin expression suggest a tumor suppressive function of melanophilin. 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 .