An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling
Bolin Tao, … , Fei Xavier Chen, Mengyun Wang
Bolin Tao, … , Fei Xavier Chen, Mengyun Wang
Published February 25, 2025
Citation Information: J Clin Invest. 2025;135(8):e179617. https://doi.org/10.1172/JCI179617.
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Research Article Genetics Oncology

An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling

Abstract

Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progression, particularly through gene expression and proteostasis control, remain unclear. By analyzing genomic data from a gastric cancer (GC) case-control study (2,117 individuals), focusing on the ubiquitin-specific protease (USP) family, we identify the SNP rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC. Mechanistically, the risk allele G is associated with enhanced USP47 expression, mediated by altered recruitment of the transcription factor GLI3 and changes in the epigenetic status at promoter. CRISPR/Cas9-mediated single-nucleotide conversion into risk allele G results in increased GLI3 binding and subsequent USP47 upregulation. The depletion of GLI3 results in a reduction of cancer-related phenotypes, similar to those observed following USP47 knockdown. Furthermore, we identify Snai1 as a deubiquitination target of USP47, explaining USP47-dependent activation of the epithelial-mesenchymal transition pathway and tumor progression. Our findings identify an important genetic predisposition that implicates the perturbation of transcription and proteostasis programs in GC, offering insights into prevention and therapeutic strategies for genetically stratified patients.

Authors

Bolin Tao, Zhenning Wang, Xuanyi Wang, Aixia Song, Jiaxian Liu, Jianan Wang, Qin Zhang, Zhaolin Chen, Zixian Wang, Wenjie Xu, Menghong Sun, Yanong Wang, Ping Zhang, Tao Xu, Gong-Hong Wei, Fei Xavier Chen, Mengyun Wang

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Figure 8

Synergistic effect of rs72856331 genotype and USP47 expression on GC patient prognosis.

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Synergistic effect of rs72856331 genotype and USP47 expression on GC pat...
(A and B) Kaplan-Meier survival curves for TCGA STAD GC patients, stratified by USP47 expression levels and rs72856331 genotypes, show significant prognostic value for USP47 in patients with the GG genotype (A) compared with AA/GA genotypes (B). (C and D) USP47 expression alone shows no prognostic significance for progression-free probability (C), but high USP47 levels in patients with the rs72856331 GG genotype correlate with decreased progression-free survival (D). (E) Model for the functional mechanism of the GC risk-associated promoter variant rs72856331 of USP47. The GC susceptibility locus rs72856331 resides in the USP47 promoter region, and risk allele G correlates with the upregulation of USP47 expression. Mechanically, the TF GLI3 exhibits a preference for binding to the risk allele G–containing promoter sequence, thereby promoting USP47 expression. USP47 upregulation in turn stabilizes Snai1, therefore activating the EMT signaling pathway and contributing to cancer-related phenotypic changes. P values assessed by log-rank test for panels A–D.