Hypoxia induced SH3GLB1 is required for NOTCH2 activation and glioblastoma development.

Glioblastoma (GBM) is the most prevalent and aggressive intracranial brain tumor in adults, with treatment options remaining limited. Aberrant activation of the Notch signaling pathway is frequently observed in GBM. However, the underlying mechanisms remain elusive. The present study identified hypoxia-induced SH3GLB1 as a transcriptional target of HIF-2A Additionally, SH3GLB1 was overexpressed in GBM tissues and associated with higher disease grading and poorer survival outcomes. Genetic depletion of SH3GLB1 reduced tumorigenic potential and impaired tumor growth in vivo. Mechanistically, SH3GLB1 is required for the nuclear localization of the NOTCH intracellular domain (N2ICD) and NOTCH2 activation. Collectively, this study highlights that SH3GLB1 is critical for sustaining GSC self-renewal under hypoxic environments and activates the NOTCH2 signaling pathway, positioning SH3GLB1 as a prognostic biomarker for GBM. Finally, SH3GLB1 depletion presents a promising therapeutic strategy for GBM patients.