HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway

Cell Death Differ. 2012 Feb;19(2):284-94. doi: 10.1038/cdd.2011.95. Epub 2011 Aug 5.


Hypoxia induces the expansion of glioblastoma stem cells (GSCs), but the mechanism underlying it is still unclear. Here, we supply evidence that hypoxia-inducible factor-1α (HIF-1α) induced activation of Notch pathway is essential for hypoxia-mediated maintenance of GSC. Either depletion of HIF-1α or inactivation of Notch signaling partly inhibits the hypoxia-mediated maintenance of GSC. Further data suggest a role for HIF-1α in the interaction and stabilization of intracellular domain of Notch (NICD), and activation of Notch signaling. The mRNA level of HIF-1α and Notch target gene FABP7 was elevated in GSC. And the STAT3 pathway responsible for the HIF-1α gene transcription, the phosphatidylinositol 3-kinase-Akt and ERK1/2, both of which are contributed to HIF-1α protein translation, are also preferentially activated in GSC. Inhibition of these pathways partly reduces the hypoxia-induced activation of the Notch pathway and subsequent GSC maintenance. Taken together, our findings suggest that HIF-1α requires Notch pathway to drive the maintenance of GSC. The activated regulation of HIF-1α makes GSC more sensitive to hypoxia-mediated maintenance. These findings enhance our understanding of mechanism of hypoxia-mediated GSC expansion and provide HIF-1α as an attractive target for glioblastoma therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Hypoxia
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Models, Biological
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Protein Binding
  • Protein Structure, Tertiary
  • Rats
  • Receptors, Notch / chemistry
  • Receptors, Notch / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction*
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Transcription, Genetic
  • Tumor Cells, Cultured


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Notch
  • STAT3 Transcription Factor
  • endothelial PAS domain-containing protein 1