Universität zu Köln

Bu, Huajie, Narisu, Narisu, Schlick, Bettina, Rainer, Johannes ORCID: 0000-0002-6977-7147, Manke, Thomas ORCID: 0000-0003-3702-0868, Schaefer, Georg, Pasqualini, Lorenza ORCID: 0000-0001-5932-8543, Chines, Peter, Schweiger, Michal R., Fuchsberger, Christian ORCID: 0000-0002-5918-8947 and Klocker, Helmut (2016). 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. Hum. Mutat., 37 (1). S. 52 - 65. HOBOKEN: WILEY. ISSN 1098-1004

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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. TG 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bu, Huajie UNSPECIFIED UNSPECIFIED UNSPECIFIED Narisu, Narisu UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlick, Bettina UNSPECIFIED UNSPECIFIED UNSPECIFIED Rainer, Johannes UNSPECIFIED orcid.org/0000-0002-6977-7147 UNSPECIFIED Manke, Thomas UNSPECIFIED orcid.org/0000-0003-3702-0868 UNSPECIFIED Schaefer, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasqualini, Lorenza UNSPECIFIED orcid.org/0000-0001-5932-8543 UNSPECIFIED Chines, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweiger, Michal R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuchsberger, Christian UNSPECIFIED orcid.org/0000-0002-5918-8947 UNSPECIFIED Klocker, Helmut UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-291512
DOI:	10.1002/humu.22909
Journal or Publication Title:	Hum. Mutat.
Volume:	37
Number:	1
Page Range:	S. 52 - 65
Date:	2016
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1098-1004
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; MELANOSOME TRANSPORT; RESPONSE ELEMENT; DNA-SEQUENCES; CELL-LINE; VARIANTS; IDENTIFICATION; TRANSCRIPTION; EXPRESSION Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/29151