Antimony Exposure Induces Bladder Cancer Metastasis Via Activation of the SUMOylation-Dependent TGF-β/Smad2/3 Axis

Antimony is an important industrial raw material, known as the "industrial monosodium glutamate", and is widely used in alloys, electronics, chemical engineering, and Other fields. Due to its extensive applications, its environmental toxicity and carcinogenic risk have attracted increasing attention. In recent years, numerous studies have reported the carcinogenic risk of antimony, but its role in bladder Cancer and the underlying molecular mechanisms have not been fully elucidated. In this study, we found that serum antimony levels were elevated in bladder Cancer patients and correlated with poor prognosis. We also demonstrated that low-dose antimony exposure significantly enhances the malignant behaviors of bladder Cancer cells, particularly their migratory/invasive abilities. Mechanistic studies revealed that antimony activates the metal response element (MRE) in the UBC9 promoter, driving SUMO2/3-dependent pan-SUMOylation. Further screening identified TGF-β Receptor as a key target of SUMOylation, whose modification leads to enhanced downstream SMAD2/3 phosphorylation, thereby inducing epithelial-mesenchymal transition (EMT). UBC9 knockdown blocked antimony-induced SUMOylation and EMT, demonstrating UBC9's central role in the SUMOylation-dependent TGF-β/SMAD2/3 signaling axis. In conclusion, this study elucidates that antimony promotes bladder Cancer progression through a SUMOylation-dependent signaling pathway, highlighting the pivotal role of post-translational modifications in heavy metal-induced carcinogenesis, and may provide a new strategy for the prevention and treatment of bladder Cancer.

Antimony; Bladder Cancer; EMT; Metastasis; SUMOylation; UBC9.