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

Ting Shen, Ting Ni, Jiaxuan Chen, Haitao Chen, Xiaopin Ma, Guangwen Cao, Tianzhi Wu, Haisheng Xie, Bin Zhou, Gang Wei, Hexige Saiyin, Suqin Shen, Peng Yu, Qianyi Xiao, Hui Liu, Yuzheng Gao, Xidai Long, Jianhua Yin, Yanfang Guo, Jiaxue Wu, Gong-Hong Wei, Jinlin Hou and Jiang De-Ke ()
Additional contact information
Ting Shen: Nanfang Hospital, Southern Medical University
Ting Ni: Fudan University
Jiaxuan Chen: Nanfang Hospital, Southern Medical University
Haitao Chen: Nanfang Hospital, Southern Medical University
Xiaopin Ma: Fudan University
Guangwen Cao: Naval Medical University
Tianzhi Wu: Southern Medical University
Haisheng Xie: Nanfang Hospital, Southern Medical University
Bin Zhou: Nanfang Hospital, Southern Medical University
Gang Wei: Fudan University
Hexige Saiyin: Fudan University
Suqin Shen: Fudan University
Peng Yu: Fudan University
Qianyi Xiao: Fudan University
Hui Liu: Guangzhou Medical University
Yuzheng Gao: Medical College of Soochow University
Xidai Long: Youjiang Medical College for Nationalities
Jianhua Yin: Naval Medical University
Yanfang Guo: Southern Medical University
Jiaxue Wu: Fudan University
Gong-Hong Wei: University of Oulu
Jinlin Hou: Nanfang Hospital, Southern Medical University
Jiang De-Ke: Nanfang Hospital, Southern Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28861-0

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