Vascular endothelial growth factor (
VEGF) is a potent inducer of angiogenesis in
oral squamous cell carcinoma (OSCC). In this study, we used the novel
DNA methyltransferase inhibitor
zebularine (Zeb) to investigate epigenetic influences on the secretion of
VEGF-A in the OSCC cell line HSC-3. Under normoxic conditions, we found that Zeb inhibited secretion in a dose-dependent manner by reducing the activity of
hypoxia-inducible factor-1α (HIF-1α). Treatment of the cells with the
proteasome inhibitor MG132 protected the HIF-1α
protein from Zeb-mediated epigenetic regulation. In addition, our study revealed that neither the PI3K/Akt nor the p53 signaling pathway is required for Zeb-induced HIF-1α degradation. In short, Zeb influenced the stability of the HIF-1α
protein and the activity of its targets, such as
VEGF, in HSC-3 cells in normoxic conditions. This study has laid the foundation for a novel anti-
cancer approach, which may find applications in molecular staging.