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

• Published in: Oncogene Vol. 33; no. 11; pp. 1458 - 1467
• Main Authors: Lee, S H, Bae, S C, Kim, K W, Lee, Y M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.03.2014; Nature Publishing Group
• Subjects: 631/67/1504/1829; 631/67/2328; Angiogenesis; Apoptosis; Cancer; Cell Biology; Cell Hypoxia - genetics; Cell Line, Tumor; Cellular control mechanisms; Core Binding Factor Alpha 3 Subunit - physiology; Epigenetics; Gastric cancer; Genetic aspects; Histones; Human Genetics; Humans; Hydroxylase; Hydroxylation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Internal Medicine; Localization; Medicine; Medicine & Public Health; Oncology; Oncology, Experimental; original-article; Proline; Prolyl hydroxylase; Prolyl Hydroxylases - metabolism; Properties; Proteins; Regulatory sequences; RNA, Messenger - genetics; Runx3 protein; Stomach cancer; Stomach Neoplasms - enzymology; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Transcription factors; Ubiquitination; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; hypoxia; HIF-1α; RUNX3; prolyl hydroxylase; angiogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.76

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.