ATXN3 deubiquitinates ZEB1 and facilitates epithelial–mesenchymal transition in glioblastoma

The activation of epithelial-mesenchymal transition (EMT) promotes glioblastoma (GBM) invasion, thereby enhancing its malignancy. Elucidating the underlying mechanisms that regulate EMT is essential for the development of effective treatments for GBM. In this study, we found that GBM tissues and cells exhibit significantly elevated expression levels of ataxin 3 (ATXN3). Functional experiments demonstrated that ATXN3 promotes the invasion, migration, and tumor growth of GBM cells by activating EMT. Mechanistically, ATXN3 was identified as a bona fide deubiquitinase for ZEB1, a key EMT-inducing transcription factor, in GBM cells. ATXN3 interacts directly with ZEB1, cleaves ubiquitin moieties from conjugated substrates and maintains the stability of ZEB1. Ectopic expression of ZEB1 significantly mitigates the inhibitory effects of ATXN3 depletion on the invasion, migration, and tumor growth of GBM cells. Furthermore, ATXN3 exhibits a positive correlation with ZEB1 expression levels and serves as a predictor of poor prognosis in human GBM specimens. Collectively, our study elucidates a critical ATXN3-ZEB1 signaling axis in EMT and invasion, thereby providing a rationale for potential therapeutic interventions against GBM.