Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha.

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 MTA1 overexpression in cancer cells with an emphasis on its potential role as a deacetylator of hypoxia-inducible factor-1alpha (HIF-1alpha). MTA1 increased the expression of HIF-1alpha 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-1alpha both in vitro and in vivo. Immunoprecipitation and acetylation assays also showed that MTA1 has deacetylation activity on HIF-1alpha in vivo. Moreover, MTA1 increased the transcriptional activity of HIF-1alpha and enhanced the expression of vascular endothelial growth factor, a target molecule of HIF-1alpha. Conditioned medium collected from MTA1 transfectants also increased angiogenesis in vitro and in vivo, probably through enhanced HIF-1alpha stabilization. These results indicate that MTA1 enhances angiogenesis by stabilization of the HIF-1alpha protein, which is closely related to the increased metastatic potential of cancer cells with high MTA1 expression.