Abstract

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.

Highlights

  • High-grade gliomas (HGG), in particular glioblastoma multiforme (GBM), are the most common and lethal primary malignant brain tumor in adults [1, 2]

  • ubiquitinspecific protease 3 (USP3) is upregulated in GBM tissues and cell lines We initially analyzed the expression of USP3 using gene expression profiling interactive analysis (GEPIA)

  • We found that USP3 is markedly overexpressed in GBM specimens and contributes to GBM cell migration and invasion via promoting Epithelial–mesenchymal transition (EMT) by stabilizing Snail

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Summary

Introduction

High-grade gliomas (HGG), in particular glioblastoma multiforme (GBM), are the most common and lethal primary malignant brain tumor in adults [1, 2]. Understanding the mechanism underlying GBM invasiveness is critical for developing more effective strategies for treating GBM.

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