Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19

Abstract

The prostate cancer (PCa) risk-associated SNP rs11672691 is positively associated with aggressive disease at diagnosis. We showed that rs11672691 maps to the promoter of a short isoform of long noncoding RNA PCAT19 (PCAT19-short), which is in the third intron of the long isoform (PCAT19-long). The risk variant is associated with decreased and increased levels of PCAT19-short and PCAT19-long, respectively. Mechanistically, the risk SNP region is bifunctional with both promoter and enhancer activity. The risk variants of rs11672691 and its LD SNP rs887391 decrease binding of transcription factors NKX3.1 and YY1 to the promoter of PCAT19-short, resulting in weaker promoter but stronger enhancer activity that subsequently activates PCAT19-long. PCAT19-long interacts with HNRNPAB to activate a subset of cell-cycle genes associated with PCa progression, thereby promoting PCa tumor growth and metastasis. Taken together, these findings reveal a risk SNP-mediated promoter-enhancer switching mechanism underlying both initiation and progression of aggressive PCa.

HNRNPAB‐regulated lncRNA‐ELF209 inhibits the malignancy of hepatocellular carcinoma

“…LncSHGL could recruit HNRNPA1 to enhance translation of calmodulin mRNAs, which would activate the PI3K/Akt pathway and repressed the mTOR/SREBP‐1C pathway . Recently, it was reported that the convergence of HNRNPAB with lncRNA‐PCAT19‐long upregulated downstream cell‐cycle genes and promoted prostate cancer development and progression . This evokes the importance of characterizing the HNRNPAB‐lncRNA mechanism.…”

“…29 Recently, it was reported that the convergence of HNRNPAB with lncRNA-PCAT19-long upregulated downstream cell-cycle genes and promoted prostate cancer development and progression. 30 This evokes the importance of characterizing the HNRNPAB-lncRNA mechanism. However, whether the hnRNP family directly regulates the expression of lncRNAs in cancer is not fully understood.…”

Decreased H19, GAS5, and linc0597 Expression and Association Analysis of Related Gene Polymorphisms in Rheumatoid Arthritis

“…Taken together, these data provide evidence for functional contribution of rs2680700 in changing linc0597 expression or stability. However, the exact roles of these two SNPs in RA still need further exploration [45,46]. Additionally, we attempted to discover the correlations of H19 expression with their gene polymorphisms in RA patients, but still no statistically significant results were found.…”

An allele-specific functional SNP associated with two autoimmune diseases modulatesIRF5expression by long-range chromatin loop formation

“…Dao et al recently verified the functional mechanisms of Epromoters referred to as the promoters with enhancer functions, suggesting that regulatory elements with dual roles as transcriptional promoters and enhancers were strongly involved in cis regulation of distal gene expression in natural context [44]. Recently, the functional SNPs with both promoter and enhancer activities were reported [45], in which different alleles of a SNP mechanistically perform different functions. In our study, rs13239597 located in the promoter region of TNPO3 functions as an allele-specific functional enhancer, which highlights dual roles of its functionality.…”