The prostate cancer risk SNP rs7463708 promotes transformation via upregulation of PCAT1 lncRNA.

  • Major finding: The prostate cancer risk SNP rs7463708 promotes transformation via upregulation of PCAT1 lncRNA.

  • Mechanism: The T risk allele of rs7463708 enhances binding of ONECUT2 and AR to the PCAT1 enhancer.

  • Impact: Prostate cancer risk–associated SNPs can promote prostate cancer via modulation of lncRNAs.

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A number of SNPs are associated with predisposition to disease and the majority of these occur outside of protein coding exons, but the molecular mechanisms by which many cancer risk–associated noncoding SNPs contribute to tumorigenesis are unknown. Through analysis of GWAS data, Guo, Ahmed, and colleagues found that prostate cancer risk–associated SNPs were enriched in regulatory regions marked by DNase I–hypersensitive sites (DHS), androgen receptor (AR) and AR cofactor occupancy, and active histone marks. Risk-associated SNPs overlapped with DHSs near lncRNA genes, suggesting that these SNPs might increase prostate cancer risk through modulation of lncRNAs, many of which are expressed in cancer but not functionally characterized. Integrative analysis identified 45 candidate lncRNAs potentially regulated by noncoding risk-associated SNPs in prostate cancer, including PCAT1, which was overexpressed in prostate cancer. Consistent with these findings, depletion of PCAT1 reduced prostate cancer cell growth in vitro and in vivo. The PCAT1 promoter was predicted to interact with the rs7463708 risk locus, a region containing 3 SNPs and overlapping with a strong DHS downstream of the PCAT1 transcription start site, which was bound by transcription factors including AR. Chromosome conformation capture confirmed that the PCAT1 promoter strongly interacted with the T risk allele, but not the G non-risk allele, of rs7463708 upon androgen treatment, and CRISPR/Cas9-mediated disruption of the rs7463708 locus prevented the PCAT1 promoter interaction and reduced PCAT1 expression, suggesting that rs7463708 regulates the activity of a PCAT1 enhancer. The T risk allele of rs7463708 exhibited increased occupancy by the transcription factors ONECUT2 and AR, which was further enhanced by androgen stimulation and resulted in increased PCAT1 expression. Moreover, PCAT1 recruited AR and LSD1 to the enhancers of two genes involved in prostate cancer, GNMT and DHCR24. In addition to identifying PCAT1 as a prostate cancer–promoting lncRNA, these findings demonstrate that risk-associated SNPs can promote transformation through regulation of lncRNAs.

Guo H, Ahmed M, Zhang F, Yao CQ, Li S, Liang Y, et al. Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer. Nat Genet 2016 Aug 15 [Epub ahead of print].

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