PDF(Pubmed)
Abstract：
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.
摘要：
全基因组关联研究（GWAS）已经确定了多个胃癌风险位点和几个蛋白质编码易感基因。然而,从这些风险位点转录的长链非编码RNA(lncRNA)在胃癌发生和进展中的作用还有待探讨.这里,我们在功能上表征了一个lncRNA，lncPSCA,作为一种新的肿瘤抑制剂，其表达受到胃癌风险相关遗传变异的精细调节。lncPSCA内含子增强子中的rs2978980T>G变化中断了转录因子RORA的结合，以等位基因特异性方式下调lncPSCA表达。LncPSCA与DDX5相互作用并通过泛素化促进DDX5降解。lncPSCA的表达增加导致DDX5的低水平，在细胞核中与DDX5结合的RNA聚合酶II（PolII）较少，从而通过PolII激活多个p53信号基因的转录。这些发现强调了在GWAS风险基因座中对lncRNAs进行功能性注释的重要性，以及调节lncRNAs作为创新癌症治疗的巨大潜力。
