An enhancer variant at 16q22.1 predisposes to hepatocellular carcinoma via regulating PRMT7 expression

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.

PRMT7 Inhibits the Proliferation and Migration of Gastric Cancer Cells by Suppressing the PI3K/AKT Pathway via PTEN

“…These results suggest that PRMT7 inhibits GC development and progression. PRMT7 is a key factor in the diagnosis of cell proliferation and distant metastasis in breast 23 , liver 24 , and lung 25 cancers, and the unlimited proliferation and distant metastasis of cancer cells are important causes of recurrence and death in patients 26 . However, the specific biological function of PRMT7 in GC has not yet been reported.…”

The role of hepatocyte nuclear factor 4α (HNF4α) in tumorigenesis

“…In a recent study on the effect of SNPs in liver cancer, the rs73613962 (T > G) site at the Protein Arginine Methyltransferase 7 (PRMT7) gene has allele-specific enhancer activity. HNF4α preferentially binds to this enhancer region with the risk allele G to activate PRMT7 transcription, and elevated PRMT7 promotes malignant phenotypes of HCC through inhibition of the p53 signaling cascade ( 25 ). Another study revealed that HNF4α bound to the -1409 to -1401 region of the circRNA_104075 promoter to induce its expression.…”

Strategies for activity analysis of single nucleotide polymorphisms associated with human diseases

“…When SNP mutations occur in regulatory elements, they may play a direct role in diseases by perturbing the function of the regulatory element and affecting the expression of target genes. At present, the mechanisms of some functional SNPs related to human complex diseases have been excavated, [12][13][14][15][16][17] and the functional roles of SNPs in human diseases will be discussed in detail below.…”