Hdac2 Promotes Cell Migration/Invasion Abilities through Hif-1 Alpha Stabilization in Human Oral Squamous Cell Carcinoma

BACKGROUND: Histone deacetylase 2 (HDAC2) expressions in oral squamous cell carcinoma (OSCC) had been implicated in advanced stage and poor prognosis. It suggests a possible link between the migration/invasion potential of oral cancer cells and the prevalent expression of HDAC2. METHODS: Five head and neck cancer (HNC) cell lines, including Ca9-22, Cal -27, HSC-3, SAS, and TW2.6, were used. Cells stably overexpressing HDAC2 and shRNA against HDAC2 were established to investigate migration/invasion ability in vitro and tumorigenesis and progression in vivo. RESULTS: We found that alterations in the HDAC2 level in OSCC cell lines modulated their invasive ability with a positive correlation. Animal model also showed that knockdown of HDAC 2 expression in SAS cells, originally containing high endogenous HDAC2 expression, resulted in decrease in tumor initiation and progression. Using high-throughput transcriptome analysis, numerous genes involved in HIF-1 alpha-associated pathways were found. At the mechanism levels, using agents to block de novo protein synthesis or prevent protein degradation by ubiquitination, we found the stability of hypoxia inducible factor 1 alpha (HIF-1 alpha) protein was maintained in OSCC cells with HDAC2 overexpression. In addition, co-immuno-precipitation assay also revealed that HDAC2-mediated HIF-1 alpha protein stability is because of direct interaction of HIF-1 alpha with von Hippel-Lindau (VHL) protein. CONCLUSIONS: Our work demonstrates that HDAC2 maintains HIF-1 alpha stability, probably at the level of protein modification, which in turn leads to the increase in cell invasion/migration ability in oral cancer progression. These findings implicate the potential of HDAC inhibitors for oral cancer therapy