E2F6 promotes glioblastoma stem cell self-renewal by repressing DUSP1 expression

Glioblastoma (GBM) is the most common and aggressive primary malignant tumor of the central nervous system, with a median overall survival from diagnosis of only 15 months, even with maximal surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy. Glioblastoma stem cells (GSCs), a subpopulation of GBM cells with self-renewal and multilineage differentiation capacities, are critical drivers of tumor growth, recurrence, metastasis, and treatment resistance. E2F transcription factor 6 (E2F6) is a member of the E2F transcription factor family and has been implicated in tumor progression and chemoresistance. However, the precise mechanisms by which E2F6 regulates GSCs remain poorly understood. In this study, we demonstrated that E2F6 is highly expressed in GBM tissues and GSCs, and its elevated expression is correlated with poor prognosis in patients with glioma. Functionally, E2F6 overexpression promotes GSC self-renewal, proliferation, and in vivo tumorigenicity, whereas E2F6 knockdown has the opposite effects. Mechanistically, E2F6 directly binds to the promoter region of dual-specificity phosphatase 1 (DUSP1) and represses its transcription. DUSP1 overexpression rescues the E2F6-induced increase in GSC stemness. Furthermore, E2F6 knockdown suppressed GSC tumorigenicity and sensitized GSCs to TMZ in an intracranial xenograft model, prolonging the survival of tumor-bearing mice. These findings identify E2F6 as a critical regulator of GSC stemness and chemoresistance through transcriptional inhibition of DUSP1, suggesting that targeting the E2F6/DUSP1 axis may represent a promising therapeutic strategy for glioblastoma.