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.
View: Text | PDF
Research Article Genetics Oncology Article has an altmetric score of 1

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

×

Figure 4

The risk allele G of rs72856331 enhances the binding ability of TF GLI3 to promote USP47 expression.

Options: View larger image (or click on image) Download as PowerPoint
The risk allele G of rs72856331 enhances the binding ability of TF GLI3 ...
(A) DNA-binding affinity scores of 5 potential TFs toward the rs72856331-containing sequence calculated using the EEL algorithm. (B and C) Correlation between GLI3 and USP47 expression levels across multiple GC datasets. P values were calculated using Pearson’s correlation test. (D) rs72856331 resides within GLI3 DNA-binding motifs. (E) EMSA with purified GLI3 protein indicating a higher affinity for the rs72856331 G allele than the A allele. (F) ChIP assay in edited HGC-27-GA cells demonstrating GLI3 enrichment at rs72856331. IgG served as a negative control, while H3K27ac was included as a positive control (n = 3). Statistical significance was calculated using 2-tailed Student’s t test. **P < 0.01; ****P < 0.0001. (G) GLI3 prefers the binding to G allele than A allele at rs72856331 revealed by ChIP Sanger sequencing. (H and I) USP47 was downregulated at both protein (H) and transcript levels (I) after partial GLI3 knockout via CRISPR/Cas9 in HGC-27 GC cells (n = 3). Statistical significance was calculated by 1-way ANOVA with Holm-Šidák multiple-comparison test. ****P < 0.0001. (J–M) USP47 expression positively correlated with GLI3 in GTEx (J), TCGA STAD (K and L), and Derrico GSE13911_Gastric dataset (M). P values assessed by Pearson’s correlation test.