Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1α

Metastasis-associated protein 1 (MTA1) is highly upregulated in cancer cells with metastatic potential; however, the molecular mechanism by which MTA1 increases the metastatic potential of cancer cells is unknown. We characterized the functional consequences of NITA I overexpression in cancer cells with an emphasis on its potential role as a deacetylator of hypoxia-inducible factor-1 alpha (HIF-1 alpha). MTA1 increased the expression of HIF-1 alpha protein, but did not increase the expression of its mRNA. Glutathione S-transferase pull-down and coimmunoprecipitation assays demonstrated direct interaction of MTA1 with HIF-1 alpha both in vitro and in vivo. Immunoprecipitation and acetylation assays also showed that MTA1 has deacetylation activity on HIF-1 alpha in vivo. Moreover, MTA1 increased the transcriptional activity of HIF-1 alpha and enhanced the expression of vascular endothelial growth factor, a target molecule of HIF-1 alpha. Conditioned medium collected from MTA1 transfectants also increased angiogenesis in vitro and in vivo, probably through enhanced HIF-1 alpha stabilization. These results indicate that MTA1 enhances angiogenesis by stabilization of the HIF-1 alpha protein, which is closely related to the increased metastatic potential of cancer cells with high MTA1 expression.