Stem-14. targeting hausp in glioma stem cells inhibits malignant growth and overcomes radioresistance of glioblastoma

Abstract Glioblastoma (GBM) is the most lethal and common type of primary brain tumor highly resistant to current treatments including radiotherapy. GBM contains heterogeneous cancer cells including glioma stem cells (GSCs) that promote malignant growth and therapeutic resistance, indicating that targeting GSCs may effectively improve GBM therapy. Here, we show that HAUSP (USP7, a deubiquitinase) is preferentially expressed by GSCs in the perivascular niches in human GBMs. Disrupting HAUSP by shRNA or its inhibitor P22077 promoted GSC differentiation, impaired GSC growth, and potently inhibited GBM malignant growth, indicating that HAUSP is required for maintaining the self-renewal and tumorigenic potential of GSCs. Moreover, pharmacological inhibition of HAUSP synergized with irradiation (IR) to suppress GBM tumor growth, suggesting that targeting HAUSP may effectively overcome GSC-driven radioresistance to improve therapeutic efficacy for GBM. Our findings uncover a novel role of HAUSP in maintaining GSC phenotypes and tumorigenic potential, and thus offer a promising druggable target for developing anti-GSC therapeutics to improve GBM treatment. Furthermore, our preclinical data suggest that inhibiting HAUSP alone or in combination with IR may prolong the survival of GBM patients.