Zebularine-induced reduction in VEGF secretion by HIF-1α degradation in oral squamous cell carcinoma

Maiko Suzuki, Fumiaki Shinohara, Hidemi Rikiishi

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)465-471
Number of pages7
JournalMolecular Medicine Reports
Volume1
Issue number4
DOIs
StatePublished - 2008

Keywords

  • Epigenetics
  • Hypoxia-inducible factor-1α
  • Oral squamous cell carcinoma
  • Vascular endothelial growth factor
  • Zebularine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Oncology
  • Cancer Research

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