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

RUNX3 overexpression significantly downregulates HIF-1α stability in gastric cancer cells.

• RUNX3 overexpression leads to decreased stability of HIF-1α under both normoxic and hypoxic conditions.
• Levels of vascular endothelial growth factor (VEGF) are reduced in cells with RUNX3 overexpression and increased in RUNX3-knockdown cells.
• Recovery of RUNX3 expression using epigenetic agents results in suppressed HIF-1α and VEGF expression under hypoxic conditions.
• RUNX3 decreases the half-life of HIF-1α protein and promotes its localization in the cytosol, leading to its ubiquitination.
• Interaction between RUNX3 and HIF-1α enhances the binding of HIF-1α to prolyl hydroxylase (PHD) 2, which facilitates proline hydroxylation and HIF-1α degradation.
• RUNX3 overexpression inhibits hypoxia-induced angiogenesis in vitro and in vivo.

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