RUNX3 inhibits hypoxia-inducible factor-1α protein stability by interacting with prolyl hydroxylases in gastric cancer cells

Oncogene. 2014 Mar 13;33(11):1458-67. doi: 10.1038/onc.2013.76. Epub 2013 Apr 1.


RUNX3 is silenced by histone modification and hypoxia-inducible factor (HIF)-1α is stabilized under hypoxia, but little is known of cross-talk between RUNX3 and HIF-1α under hypoxia. In the present study, the authors investigated the effect of RUNX3 on HIF-1α stability in gastric cancer cells. RUNX3 overexpression was found to downregulate HIF-1α stability under normoxic and hypoxic conditions. Furthermore, the activity of a luciferase reporter containing five copies of vascular endothelial growth factor (VEGF) promoter hypoxia-responsive element (5 × HRE) and the amount of secreted VEGF, were diminished in RUNX3-expressing but increased in RUNX3-knockdown cells. When expression of RUNX3 was recovered using epigenetic reagents the expressions of HIF-1α and VEGF were clearly suppressed under hypoxic conditions. RUNX3 also significantly attenuated the half-life of HIF-1α protein, and induced the cytosolic localization and ubiquitination of HIF-1α. In addition, RUNX3 directly interacted with the C-terminal activation domain of HIF-1α and prolyl hydroxylase (PHD) 2 and enhanced the interaction between HIF-1α and PHD2, which potentiated proline hydroxylation and promoted the degradation of HIF-1α. Furthermore, RUNX3 overexpression significantly inhibited hypoxia-induced angiogenesis in vitro and in vivo. Taken together, these results suggest that RUNX3 destabilizes HIF-1α protein by promoting the proline hydroxylation of HIF-1α through binding to HIF-1α/PHD2. RUNX3 appears to be a novel suppressor of HIF-1α and of hypoxia-mediated angiogenesis in gastric cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia / genetics
  • Cell Line, Tumor
  • Core Binding Factor Alpha 3 Subunit / physiology*
  • Humans
  • Hydroxylation
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Prolyl Hydroxylases / metabolism*
  • RNA, Messenger / genetics
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Ubiquitination
  • Vascular Endothelial Growth Factor A / genetics


  • Core Binding Factor Alpha 3 Subunit
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Runx3 protein, human
  • Vascular Endothelial Growth Factor A
  • Prolyl Hydroxylases