State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
School of Life Sciences, Central South University, 510006, Changsha, China.
Nat Commun. 2022 Mar 9;13(1):1232. doi: 10.1038/s41467-022-28861-0.
Most cancer causal variants are found in gene regulatory elements, e.g., enhancers. However, enhancer variants predisposing to hepatocellular carcinoma (HCC) remain unreported. Here we conduct a genome-wide survey of HCC-susceptible enhancer variants through a three-stage association study in 11,958 individuals and identify rs73613962 (T > G) within the intronic region of PRMT7 at 16q22.1 as a susceptibility locus of HCC (OR = 1.41, P = 6.02 × 10). An enhancer dual-luciferase assay indicates that the rs73613962-harboring region has allele-specific enhancer activity. CRISPR-Cas9/dCas9 experiments further support the enhancer activity of this region to regulate PRMT7 expression. Mechanistically, transcription factor HNF4A binds to this enhancer region, with preference to the risk allele G, to promote PRMT7 expression. PRMT7 upregulation contributes to in vitro, in vivo, and clinical HCC-associated phenotypes, possibly by affecting the p53 signaling pathway. This concept of HCC pathogenesis may open a promising window for HCC prevention/treatment.
大多数癌症因果变异存在于基因调控元件中，例如增强子。然而，易患肝细胞癌 (HCC) 的增强子变异仍未报道。在这里，我们通过在 11958 个人中进行三阶段关联研究，对 HCC 易感增强子变异进行了全基因组调查，在 16q22.1 处的 PRMT7 内含子区域中鉴定出 rs73613962（T > G）作为 HCC 的易感位点 (OR = 1.41, P = 6.02 × 10)。增强子双荧光素酶测定表明，rs73613962 携带区域具有等位基因特异性增强子活性。CRISPR-Cas9/dCas9 实验进一步支持该区域的增强子活性来调节 PRMT7 表达。在机制上，转录因子 HNF4A 结合到该增强子区域，优先结合风险等位基因 G，以促进 PRMT7 表达。PRMT7 的上调有助于体外、体内和临床 HCC 相关表型，可能通过影响 p53 信号通路。这种 HCC 发病机制的概念可能为 HCC 的预防/治疗开辟了一个有希望的窗口。
