2. Academic Validation
  3. An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling

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

  • J Clin Invest. 2025 Feb 25:e179617. doi: 10.1172/JCI179617.
Bolin Tao 1,  Zhenning Wang 1,  Xuanyi Wang 1,  Aixia Song 1,  Jiaxian Liu 2,  Jianan Wang 1,  Qin Zhang 3,  Zhaolin Chen 4,  Zixian Wang 5,  Wenjie Xu 5,  Menghong Sun 6,  Yanong Wang 7,  Ping Zhang 1,  Tao Xu 8,  Gong-Hong Wei 3,  Fei Xavier Chen 1,  Mengyun Wang 1
Affiliations

Affiliations

  • 1 Cancer Institute, Department of Radiation Oncology, Fudan University, Shanghai, China.
  • 2 Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China.
  • 3 Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medic, Biocenter Oulu, University of Oulu, Oulu, Finland.
  • 4 Department of Pharmacy, The First Affiliated Hospital of USTC, Division of , University of Science and Technology of China, Hefei, China.
  • 5 MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Bioc, Shanghai Medical College of Fudan University, Shanghai, China.
  • 6 Department of Pathology, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 7 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
  • 8 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.
PMID: 39998882 DOI: 10.1172/JCI179617
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 single nucleotide polymorphism (SNP) rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC (OR = 0.78, P = 0.015). 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 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.

Keywords

Gastric cancer; Genetic variation; Genetics; Oncology; Transcription.

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