An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling
机构：[1]Cancer Institute, Department of Radiation Oncology, Fudan University Shanghai Cancer Center. Department of Oncology, Shanghai Medical College, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetic, Fudan University, Shanghai, China.[2]Department of Oncology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China.四川省人民医院[3]Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China.[4]Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.[5]Department of Pharmacy, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China.[6]MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.[7]Department of Pathology, Fudan University Shanghai Cancer Center. Department of Oncology, Shanghai Medical College, Fudan University, and[8]Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.[9]Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.
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.
基金：
We would like to thank Midie Xu, Yanzi Gu, Weiwei Jing, and
Guangqi Qin from the Institute of Pathology, Fudan University,
Shanghai, for their outstanding support in clinical sample collection.
This research was supported by grants from the National Key
R&D Program of China (2021YFA1301700), the National Natural
Science Foundation of China (32070636, 82073082, 82311530050),
Jane ja Aatos Erkon säätiö, and Sigrid Juséliuksen Säätiö.
语种：
外文
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出版当年[2025]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2025]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]Cancer Institute, Department of Radiation Oncology, Fudan University Shanghai Cancer Center. Department of Oncology, Shanghai Medical College, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetic, Fudan University, Shanghai, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Tao Bolin,Wang Zhenning,Wang Xuanyi,et al.An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling[J].The Journal Of Clinical Investigation.2025,135(8):doi:10.1172/JCI179617.
APA：
Tao Bolin,Wang Zhenning,Wang Xuanyi,Song Aixia,Liu Jiaxian...&Wang Mengyun.(2025).An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling.The Journal Of Clinical Investigation,135,(8)
MLA：
Tao Bolin,et al."An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling".The Journal Of Clinical Investigation 135..8(2025)
医学