Therapeutic Potential of Targeting USP2 in Pediatric Group 3 and 4 Medulloblastomas: Insights from In Silico, Ex Vivo, and In Vitro Studies.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is classified into four molecular groups: WNT, SHH, G3, and G4. G3 and G4 MBs are characterized by poor prognosis and high metastatic potential. Although USP2 (ubiquitin-specific peptidase 2) has been described as a prognostic biomarker and a promising therapeutic target in several cancer types, its role in the pathogenesis of G3 and G4 MBs remains unexplored. In this study, USP2 expression was investigated through in silico analyses, public datasets (GSE85217), and tumor samples from 54 pediatric MB patients. In addition, the effects of USP2 inhibition were evaluated in two G3/G4 MB cell lines (D283 Med and USP-13) using ML364, a selective USP2 inhibitor. USP2 was overexpressed in G3 and G4 MBs and was associated with metastasis and unfavorable clinical outcomes. Furthermore, ML364 treatment reduced USP2 protein expression level, as well as cell viability, migration, invasion, and colony-forming capacity in both cell lines. These findings indicate that USP2 is upregulated in pediatric G3 and G4 MBs and support its potential role as a biomarker of poor prognosis and a therapeutic target in these molecular subgroups.