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Prostate Cancer Risk SNPs in Androgen Receptor Target Sites

ABSTRACT: We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found 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 of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin .

ORGANISM(S): Homo sapiens

PROVIDER: GSE70679 | GEO | 2015/07/10

SECONDARY ACCESSION(S): PRJNA289344

REPOSITORIES: GEO

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Prostate Cancer Risk SNPs in Androgen Receptor Target Sites

Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found 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 of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin . Genomic profile of androgen receptor binding sites of androgen or vehicle treated DUCaP cells using ChIP-seq. IgG precipiated DNAs from both treatments served as controls.

2015-07-10 | E-GEOD-70679 | biostudies-arrayexpress

Prostate Cancer Risk SNPs enriched in Androgen Receptor Binding Sites

Project description:Genome-wide association studies (GWAS) have identified dozens of genomic loci, whose single nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the biological functions of these common genetic variants and the mechanisms to increase disease risk are largely unknown. We integrated chromatin-IP coupled sequencing (ChIP-seq) and microarray expression profiling in the TMPRSS2-ERG gene rearrangement positive DuCaP cell model with the NHGRI GWAS PCa risk SNPs catalog, in an attempt to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Among the 48 GWAS index SNPs and 2,702 linked SNPs defined by the 1000G project 104 were found to be localized in the AR ChIP-seq peaks. Of these risk SNPs, rs11891426 T/G in the 7th intron of its host gene melanophilin (MLPH) was found located within a putative auxiliary ARE motif, which we found enriched in the neighborhood of canonical ARE motifs. Exchange of T to G attenuated the transcriptional activity of the MLPH-ARBS in a reporter gene assay. The expression of MLPH protein in tissue samples from prostate cancer patients was significantly lower in those with the G compared to the T allele. Moreover, a significant positive correlation of AR and MLPH protein expression levels was also confirmed in tissue samples. These results unravel a hidden link between AR and a functional PCa risk SNP rs11891426, whose allele alteration affects androgen regulation of its host gene MLPH. This study shows the power of integrative studies to pin down functional risk SNPs and justifies further investigations.

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Project description:Prostate cancer (PCa) is the most frequently diagnosed cancer in Canadian men and is the third cause of cancer mortality. PCa initiation and growth is driven by the androgen receptor (AR). AR is activated by androgens such as testosterone and controls prostatic cell proliferation and survival. We sought to characterize global AR signalling networks. We performed BioID proximity labeling proteomics in androgen-dependent LAPC4 cells to delineate AR protein interaction networks. We report the identification of 32 AR associated proteins in non-stimulated cells. Strikingly, the AR signalling network increased to 183 and 201 proteins, upon 24h or 72h androgenic stimulation, respectively. Among this group, we identified 215 proteins that were not previously reported as AR interactors. Interestingly, these AR associated proteins were previously reported to be involved in DNA metabolism, RNA processing and RNA polymerase II transcription. Moreover, we identified 44 transcription factors, such as the Krüppel-like factor 4 (KLF4), which was specifically revealed in androgen-stimulated cells. We determined that KLF4 acts as a repressor of AR target genes transcription in PCa cells. Taken together, our data report the largest high-confidence proximity networks for AR in PCa cells.

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