Regulation of Circadian Rhythm of Human Vascular Endothelial Growth Factor by Circadian Rhythm of Hypoxia Inducible Factor-1α : Implication for Clinical Use as Anti-Angiogenic Therapy

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Angiogenesis is essential for tumor growth and metastasis, therefore, inhibition of angiogenesis has emerged as a new therapy to treat cancers. Although vascular endothelial cell growth factor (VEGF) induces tumor growth and metastasis by its angiogenic property, the mechanism(s) of circadian rhythm in angiogenesis has not been fully analyzed. Here we revealed that VEGF mRNA expression level, protein expression level and its promoter activity belonged to circadian rhythm in human colon carcinoma cell line, HCT116 cells. HIF (hypoxia inducible factor)-1α also underwent circadian oscillation at levels of mRNA and promoter activity. Co-transfection of Bmal1 and Clock enhanced HIF-1α luciferase activity, but not VEGF luciferase activity, indicating that VEGF is not a direct target of Bmal1/Clock. However, inhibition of HIF-1α by chrysin resulted in disappearance of VEGF circadian oscillation, suggesting that HIF-1α is involved in the regulation of the VEGF expression. Moreover, circadian oscillation of VEGF and HIF-1α was induced by 100 nM of dexamethasone. These results suggest the link between the circadian oscillation between VEGF and HIF-1α, raising a possible strategy for chronotherapy in clinic.