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-1 alpha and Hif-2 alpha, 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-2 alpha interacted with NICD and repressed the activity of Notch signaling, in contrast to the role of Hif-1 alpha in Notch signaling. Together, our findings suggest that Hif-1 alpha and Hif-2 alpha, 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.