Hif-1α and Hif-2α differentially regulate Notch signaling through competitive interaction with the intracellular domain of Notch receptors in glioma stem cells.

Hypoxia contributes to GSC expansion principally through Hif-1α and Hif-2α, but how these two factors work together has not been completely understood. We show that hypoxia promoted proliferation, self-renewal and inhibited the conversion of GSCs into INP-like cells through activating Notch signaling. Further data suggested that Hif-2α interacted with NICD and repressed the activity of Notch signaling, in contrast to the role of Hif-1α in Notch signaling. Together, our findings suggest that Hif-1α and Hif-2α competitively bind to NICD and dynamically regulate the activation of Notch signaling in GSCs likely depending on different oxygen tensions, providing improved therapeutic opportunities for malignant gliomas.