Risk-associated SNPs promote prostate cancer through modulating lncRNA expression


The prostate cancer risk-associated T allele at rs7463708 results in increased expression of PCAT1 through modulating ONECUT2 and AR binding at a distal enhancer. PCAT1 recruits AR and LSD1 to GNMT and DHCR24 enhancers to activate transcription of these genes.

Long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with genomic data and SNP data from prostate cancer genome-wide association studies (GWAS), researchers at the Princess Margaret Cancer Center identified 45 candidate lncRNAs associated with risk to prostate cancer. They further evaluated the mechanism underlying the top hit, PCAT1, and found that a risk-associated variant at rs7463708 increases binding of ONECUT2, a novel androgen receptor (AR)-interacting transcription factor, at a distal enhancer that loops to the PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment. In addition, PCAT1 interacts with AR and LSD1 and is required for their recruitment to the enhancers of GNMT and DHCR24, two androgen late-response genes implicated in prostate cancer development and progression. PCAT1 promotes prostate cancer cell proliferation and tumor growth in vitro and in vivo. These findings suggest that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting prostate transformation.

Guo H et al. (2016) Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer. Nat Genet 48(10):1142-50. [abstract]

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