Ubiquitin-Specific Protease 3 Promotes Glioblastoma Cell Invasion and Epithelial–Mesenchymal Transition via Stabilizing Snail

Epithelial-mesenchymal transition (EMT) represents one of the most important events in the invasion of glioblastomas (GBM); therefore, better understanding of mechanisms that govern EMT is crucial for the treatment of GBMs. In this study, we report that the deubiquitinase ubiquitin-specific protease 3 (USP3) is significantly upregulated in GBMs and correlates with a shorter median overall and relapse-free survival. Silencing of USP3 attenuates the migration and invasion abilities of GBM cells in vitro and tumor growth in an orthotopic xenograft mouse model. Mechanistically, we identify USP3 as a bona fide deubiquitinase for Snail, a master transcription factor that promotes EMT, in GBM cells. USP3 interacts directly with Snail and stabilizes Snail via deubiquitination. Ectopic expression of Snail could largely rescue the inhibitory effects of USP3 depletion on migration, invasion, and tumor growth of GBM cells. In addition, we found that USP3 strongly correlates with Snail expression in primary human GBM samples. Overall, our findings reveal a critical USP3-Snail signaling axis in EMT and invasion, and provide an effective therapeutic approach against GBM. IMPLICATIONS: Our study establishes USP3-mediated Snail stabilization as an important mechanism underlying GBM invasion and progression, and provides a rationale for potential therapeutic interventions in the treatment of GBM.