JOSD1 stabilizes SULF1 to activate Wnt7B-FZD1 signaling in gastric cancer

  • Transl Oncol. 2026 Jul:69:102813. doi: 10.1016/j.tranon.2026.102813.
Lixin Liu  1 ,  Zhijian Ma  2 ,  Yaqing Zhang  3 ,  Zhenzhen Ye  4 ,  Hongbin Li  5 ,  Wengui Shi  6 ,  Zuoyi Jiao  7
Affiliations
  • 1. The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Lanzhou University, Lanzhou 730030, China; Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou 730030, China.
  • 2. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 3. Department of Gynecology, Gansu Provincial Maternity and Child-care Hospital, Lanzhou 730050, China.
  • 4. The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou 730030, China.
  • 5. School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China.
  • 6. Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730030, China.
  • 7. Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China. Electronic address: [email protected].
PMID: 42140034 DOI: 10.1016/j.tranon.2026.102813
Abstract

Background: Aberrant activation of Wnt/β-catenin signaling is a major driver of Gastric Cancer (GC) progression. However, the upstream mechanisms that sustain receptor-ligand engagement within this pathway remain insufficiently characterized.

Methods: Comprehensive analyses of GC cohorts and tissue microarrays were performed to evaluate Josephin Domain Containing 1 (JOSD1) expression and its clinical significance. The impact of JOSD1 on cell proliferation, migration, invasion, Apoptosis, and epithelial mesenchymal transition (EMT) was examined in vitro employing CCK-8, colony formation, Transwell, flow cytometry, Western blotting, and immunofluorescence assays. Subcutaneous xenograft models were used to assess the effects of JOSD1 on tumor growth in vivo. Mechanistic studies, including co-immunoprecipitation, ubiquitination, and rescue experiments, were employed to elucidate the molecular relationship between JOSD1, Heparan sulfate 6-O-endosulfatase 1 (SULF1), and the Wnt7B/FZD1/β-catenin signaling axis.

Results: JOSD1 expression was markedly elevated in GC tissues (log₂ FC > 1, FDR < 0.05) and correlated with advanced stage (P < 0.05) and poor patient prognosis (HR > 1, log-rank P < 0.05). Functionally, JOSD1 promoted GC cell proliferation, invasion, and EMT, while inhibiting Apoptosis (P < 0.05). Mechanistically, JOSD1 functioned as a critical Deubiquitinase that stabilized SULF1. Stabilized SULF1 directly bound the Wnt co-receptor Frizzled class receptor 1 (FZD1) and facilitated Wnt7B-FZD1 complex formation (P < 0.05), thereby activating canonical Wnt/β-catenin signaling and inducing β-catenin nuclear accumulation (P < 0.05). Ubiquitination and rescue assays confirmed that JOSD1-driven oncogenic effects were strictly dependent on SULF1 stabilization (P < 0.05). In vivo modulation of the JOSD1-SULF1 axis significantly altered tumor growth, apoptotic activity, EMT marker expression, and Wnt pathway activation (P < 0.05).

Conclusion: JOSD1 functions as a critical Deubiquitinase that stabilizes SULF1 to activate Wnt/β-catenin signaling, thereby driving GC progression. Targeting the JOSD1-SULF1-Wnt7B/FZD1/β-catenin axis may provide a promising therapeutic strategy for patients with GC.

Keywords
Deubiquitination; Epithelial-Mesenchymal transition; Gastric cancer; JOSD1; SULF1; Wnt/β-catenin.
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