LncPSCA in the 8q24.3 risk locus drives gastric cancer through destabilizing DDX5

Genome-wide association studies (GWAS) have identified multiple gastric cancer risk loci and several protein-coding susceptibility genes. However, the role of long-noncoding RNAs (lncRNAs) transcribed from these risk loci in gastric cancer development and progression remains to be explored. Here, we functionally characterize a lncRNA, lncPSCA, as a novel tumor suppressor whose expression is fine-regulated by a gastric cancer risk-associated genetic variant. The rs2978980 T > G change in an intronic enhancer of lncPSCA interrupts binding of transcription factor RORA, which down-regulates lncPSCA expression in an allele-specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation through ubiquitination. Increased expression of lncPSCA results in low levels of DDX5, less RNA polymerase II (Pol II) binding with DDX5 in the nucleus, thus activating transcription of multiple p53 signaling genes by Pol II. These findings highlight the importance of functionally annotating lncRNAs in GWAS risk loci and the great potential of modulating lncRNAs as innovative cancer therapy. Synopsis The long non-coding RNA lncPSCA is a tumor suppressor encoded at the 8q24.3 gastric cancer risk locus. LncPSCA promotes DDX5 degradation, reduces RNA polymerase II interactions with DDX5, and activates transcription of multiple p53 signaling genes. LncRNA lncPSCA is a novel tumor suppressor at the 8q24.3 gastric cancer risk locus. The rs2978980 risk polymorphism interrupts RORA binding to a lncPSCA enhancer and down-regulates its expression in an allele-specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation via ubiquitination. Graphical Abstract The long non-coding RNA lncPSCA is a tumor suppressor encoded at the 8q24.3 gastric cancer risk locus. LncPSCA promotes DDX5 degradation, reduces RNA polymerase II interactions with DDX5, and activates transcription of multiple p53 signaling genes.