TRAP1 promotes self-renewal and tumorigenicity of glioblastoma stem cells by inhibiting Notch1 ubiquitination.

Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system and is classified as Grade IV in the World Health Organization (WHO)'s brain tumor categorization. Even with standard treatment protocols, the median overall survival of newly diagnosed GBM patients is only 14.6 months. Glioblastoma stem cells (GSCs), a small subset of GBM cells with self-renewal and multilineage differentiation capacities, are considered critical contributors to the strong tumor heterogeneity, diffuse progression, and recurrence of GBM. Investigating signaling pathways associated with GSCs to identify novel therapeutic strategies targeting these cells is of paramount importance. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the 90 kDa heat shock protein (Hsp90) family, has been implicated in the maintenance or regulation of GSC stemness. However, its underlying mechanisms remain poorly understood. In this study, we demonstrated that TRAP1 is highly expressed in GSCs and that its elevated expression correlates with enhanced self-renewal capacity and in vivo tumorigenicity of GSCs. Mechanistically, TRAP1 interacts with Notch1 and inhibits its ubiquitination, thereby promoting GSC stemness. Knockdown of TRAP1 expression reduced the self-renewal capacity and in vivo tumorigenicity of GSCs, consequently improving the prognosis of tumor-bearing mice. These findings suggest that targeting TRAP1 may represent a viable strategy to improve outcomes for glioblastoma patients in the future.