Abstract
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 × 10−10). 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.
Highlights
Most cancer causal variants are found in gene regulatory elements, e.g., enhancers
We screened single-nucleotide polymorphisms (SNPs) that potentially change enhancer activity by the following criteria: (1) the SNPs are significantly associated with gene expression through cis-expression quantitative trait loci analysis using the Genotype-Tissue Expression (GTEx) liver tissue data[16]; (2) the SNPs are located in the enhancer-associated histone modification regions (monomethylation at histone H3 lysine 4 (H3K4me1), and acetylation of histone H3 at lysine 27 (H3K27ac)) in the liver hepatoma cell line HepG217; (3) the SNPs are within the binding motif of transcription factors as transcription factor binding is usually required for enhancer activity[18]
Multiple susceptible genetic variants associated with hepatocellular carcinoma (HCC) pathogenesis have been discovered using genome-wide association studies (GWASs) by both our group and other researchers over the past few years[3–10]
Summary
Most cancer causal variants are found in gene regulatory elements, e.g., enhancers. enhancer variants predisposing to hepatocellular carcinoma (HCC) remain unreported. Gao et al discovered that a GWAS-identified prostate cancer-susceptible SNP rs11672691 resides in an enhancer element and alters the binding site of transcription factor HOXA2. All demonstrated that the casual SNP resides in a regulatory element and affects the expression of the targeted gene(s) by altering the binding affinity of a certain transcription factor. The regulated target genes further influence cancer initiation and progression It remains unknown whether there are HCC-susceptible SNP(s) present in the regulatory elements, such as enhancers, and what are the underlying mechanisms by which such susceptible SNP(s) drive HCC development. In the following series of functional experiments, we demonstrate that rs73613962 regulates the expression of its host gene PRMT7 by affecting the binding preference of the transcription factor HNF4A to the alleles of rs73613962. We investigate that upregulation of PRMT7 contributes to HCC-related phenotypes possibly via p53 signaling pathway
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