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.
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.
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DOI：
10.1002/humu.22909
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发表时间：
2016-01
期刊：
影响因子：
3.9
通讯作者：
Klocker H
中科院分区：
文献类型：
--
作者：
Bu H;Narisu N;Schlick B;Rainer J;Manke T;Schäfer G;Pasqualini L;Chines P;Schweiger MR;Fuchsberger C;Klocker H
全基因组关联研究已经确定了基因组基因座，其单核苷酸多态(SNPs)易患前列腺癌(Pca)。然而，这些变体中的大多数机制在很大程度上是未知的。我们在TMPRSS2-ERG基因重排阳性的DuCaP细胞中结合染色质免疫沉淀耦合测序和微阵列表达谱与GWASPCA风险SNPs目录相结合，以确定定位于功能性雄激素受体结合位点(ARBS)的疾病易感性SNPs。在48个GWAS指数风险SNPs和3917个连锁SNP中，发现80个位于ARBS。其中，亲黑素基因(MLPH)内含子中的rs11891426：T>；G位于一个新的辅助AR结合基序中，该基序富含在典型的雄激素反应元件附近。在AR报告基因分析中，T→G交换减弱了ARB的转录活性。与T等位基因相比，G等位基因在前列腺癌中的表达显著降低，且与AR蛋白的表达显著相关。前列腺癌风险分布良好的患者前列腺组织中的亲黑素水平较高，表明有肿瘤抑制作用。这些结果揭示了AR和一个可能的PCa风险SNP之间的隐藏联系，SNP的等位基因改变影响其宿主基因MLPH的雄激素调节。
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.