The O-glycosylation of SH3PX1 accelerates the progression of lung adenocarcinoma by modulating cell proliferation and glycolysis.

Abstract

Lung adenocarcinoma (LUAD) remains a significant clinical challenge due to its high rate of recurrence, and the molecular mechanisms driving its malignant progression remain incompletely understood. The functional role of SH3PX1 in LUAD was assessed using in vitro assays (CCK-8, colony formation, EdU, cell cycle, and metabolic assays) as well as in vivo xenograft models. Bioinformatic analysis revealed that SH3PX1 is upregulated in LUAD, and its elevated expression is associated with poor patient prognosis. In LUAD cell lines, overexpression of SH3PX1 promoted cell proliferation and glycolysis, whereas SH3PX1 knockdown produced the opposite effects. Moreover, SH3PX1 enhanced tumor growth in vivo. Mechanistically, SH3PX1 was identified to interact with GALNT2, a key enzyme responsible for initiating protein O-glycosylation. We further demonstrated that the stability of SH3PX1 was regulated by GALNT2-mediated O-glycosylation at serine 92 (S92). Additionally, the pro-tumorigenic effects of GALNT2 on LUAD cell malignancy were suppressed upon SH3PX1 knockdown, indicating that SH3PX1 serves as a downstream mediator of GALNT2 in LUAD pathogenesis. Collectively, these findings provide that SH3PX1 acts as a regulator of LUAD malignancy through GALNT2-mediated O-glycosylation and stabilization, suggesting that targeting SH3PX1 may represent a potential therapeutic strategy for LUAD.