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

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.

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.

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).

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.