Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells

Tumor hypoxia is associated with poor patient survival and is a characteristic of glioblastoma. Notch signaling is implicated in maintaining glioma stem-like cells (GSCs) within the hypoxic niche, although the molecular mechanisms linking hypoxia to Notch activation have not been clearly delineated. Here we show that Vasorin is a critical link between hypoxia and Notch signaling in GSCs. Vasorin is preferentially induced in GSCs by a HIF1α/STAT3 co-activator complex and stabilizes Notch1 protein at the cell membrane. This interaction prevents Numb from binding Notch1, rescuing it from Numb-mediated lysosomal degradation. Thus, Vasorin acts as a switch to augment Notch signaling under hypoxic conditions. Vasorin promotes tumor growth and reduces survival in mouse models of glioblastoma, and its expression correlates with increased aggression of human gliomas. These findings provide mechanistic insights into how hypoxia promotes Notch signaling in glioma and identify Vasorin as a potential therapeutic target. [Display omitted] •Vasorin maintains glioma stem-like cells (GSCs) in the hypoxic niche•HIF1α/STAT3 co-activator complex induces Vasorin expression selectively in GSCs•Vasorin binds to and regulates membranous Notch1 turnover•Vasorin expression correlates with glioma aggressiveness Man et al. show that hypoxia preferentially augments Notch signaling in glioma stem-like cells by inducing the HIF1/STAT3 target gene Vasorin. Vasorin functions as a competitive inhibitor of Numb to reduce Notch turnover, augmenting Notch signaling under hypoxic stress.