USP18 deubiquitinates and stabilizes Twist1 to promote epithelial-mesenchymal transition in glioblastoma cells.

Aberrant activation of epithelial-mesenchymal transition (EMT) pathway drives the invasion and migration of multiple cancers including glioblastoma (GBM). Clinical interventions focused on inhibiting EMT are of increasing interest in the treatment of GBM. In the present study, we discovered that glioma tissues and cells, especially GBMs show significantly up-modulated ubiquitin-specific protease 18 (USP18) expression. Functionally, decreased USP18 expression attenuated GBM cell invasion and migration through repressing EMT. Moreover, a critical EMT-inducing transcription factor Twist1 that activates EMT, was identified as a downstream target of USP18. Mechanistically, USP18 interacts with Twist1, removes its ubiquitination off, and subsequently stabilizes it. Short hairpin RNA-mediated downregulation of USP18 accelerates Twist1 degradation, resulting in the inhibition of GBM cell invasion and migration in vitro and in a nude mouse model. Importantly, reconstituted expression of Twist1 almost completely rescues the inhibitory effect of USP18 depletion on GBM cell invasion, migration and tumor formation. Clinically, the expression levels of USP18 and Twist1 are positively relevant in GBM specimens, and high expression of USP18 correlates with patient's poor outcome. Finally, our findings unveil the crucial role of USP18 on GBM malignancy. Targeting USP18-Twist1 regulatory axis may open a novel avenue for GBM treatment.