Arsenic induced deubiquitination modification of PLCE1 in a de-SUMO-dependent manner to affect malignant behavior in bladder epithelial cells.

Arsenic, commonly found as an environmental pollutant, poses significant health threats and has become a worldwide public health concern. Extended exposure to arsenic is linked to the development of multiple cancers, particularly bladder cancer. In this study, a rat bladder tumor model was established by combined administration of N-methyl-N-nitrosourea (MNU) and sodium arsenite (NaAsO₂), with MNU serving as a carcinogen and NaAsO₂ as a promoter. Additionally, we constructed arsenic-treated cell model using the SV-HUC-1 human uroepithelial cell line, which was subjected to NaAsO₂ treatment for 40 weeks. This study confirmed that arsenic promoted bladder tumorigenesis induced by MNU in rats. The expression of PLCE1 protein was significantly upregulated in arsenic-treated bladder epithelial cells, and the inhibition of PLCE1 effectively ameliorated the arsenic associated malignant phenotype. Mechanistically, the elevated protein levels of PLCE1 were jointly regulated by OTUD7B-mediated deubiquitination and SENP1-mediated deSUMOylation. Notably, SENP1-mediated deSUMOylation further promoted the deubiquitination modification of PLCE1. Functional experiments demonstrated that either the inactivation of OTUD7B enzyme activity (C194S mutation) or the knockdown of SENP1 significantly alleviated the malignant behavior of bladder epithelial cells induced by inorganic arsenic. This "dual-modification" model provides a new paradigm for studying the carcinogenic mechanisms of environmental toxicants.