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Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1.

The EMBO journal | Mar 22, 2006

http://www.ncbi.nlm.nih.gov/pubmed/16511565

The expression of metastasis-associated protein 1 (MTA1) correlates well with tumor metastases; however, the associated molecular mechanism is not fully understood. Here, we explored the possibility of cross-talk between MTA1 and hypoxia-inducible factor-1alpha (HIF-1alpha), a key regulator of angiogenic factors. We observed that the expression of MTA1 was strongly induced under hypoxia in breast cancer cell lines such as MCF-7 and MDA-MB-231. When MTA1 was overexpressed, the transcriptional activity and stability of HIF-1alpha protein were enhanced. MTA1 and HIF-1alpha are physically associated in vivo and they were localized completely in the nucleus when coexpressed. MTA1 induced the deacetylation of HIF-1alpha by increasing the expression of histone deacetylase 1 (HDAC1). MTA1 counteracted to the action of acetyltransferase, ARD1, and it did not stabilize the HIF-1alpha mutant that lacks the acetylation site, K532R. These results indicate that acetylation is the major target of MTA1/HDAC1 function. Collectively, our data provide evidence of a positive cross-talk between HIF-1alpha and MTA1, which is mediated by HDAC1 recruitment, and indicate a close connection between MTA1-associated metastasis and HIF-1-induced tumor angiogenesis.

Pubmed ID: 16511565 RIS Download

Mesh terms: Acetylation | Acetyltransferases | Anoxia | Blotting, Western | Cell Nucleus | Female | Gene Expression Regulation | Histone Deacetylase 1 | Histone Deacetylase Inhibitors | Histone Deacetylases | Humans | Hypoxia-Inducible Factor 1, alpha Subunit | Immunoprecipitation | N-Terminal Acetyltransferase A | N-Terminal Acetyltransferase E | RNA, Small Interfering | Repressor Proteins | Transcription, Genetic | Transcriptional Activation | Tumor Cells, Cultured

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