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

Publication date: Available online 30 November 2017
Source:Cell Stem Cell
Author(s): Jianghong Man, Xingjiang Yu, Haidong Huang, Wenchao Zhou, Chaomei Xiang, Haohao Huang, Lucio Miele, Zhenggang Liu, Gurkan Bebek, Shideng Bao, Jennifer S. Yu
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.

Graphical abstract

Teaser

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.


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