Yoo YG, Kong G, Lee MO.. Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO J 25: 1231-1241

College of Pharmacy and Bio-MAX Institute, Seoul National University, Seoul, Korea.
The EMBO Journal (Impact Factor: 10.43). 04/2006; 25(6):1231-41. DOI: 10.1038/sj.emboj.7601025
Source: PubMed


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.

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Available from: Mi-Ock Lee, Nov 24, 2014
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    • "As transcriptional cofactors, several histone modifying enzymes have been reported to regulate HIF-1 transactivation. The histone acetyltransferase p300 and histone deacytylases (HDACs) regulate HIF-1 transcriptional activity by acetylation/deacetylation [17] [18] [19] [20] [21] [22]. The histone methyltransferase G9a and histone demethylase jumonji domain containing protein 1A (JMJD1A) and JMJD2C regulate HIF-1 transactivation through methylation/demethylation of histone and non-histone proteins [23] [24] [25]. "
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    • "The binding of E7 to HIF-1α was directly inhibited through deletion of the N-terminus pRb binding domain of E7. Many HDACs (including HDAC1, 4, and 7) enhance HIF-1 activity on their own (Kato et al., 2004; Qian et al., 2006; Yoo et al., 2006), however the authors hypothesized that binding of HPV E7 to HIF-1α allows for the displacement of these HDAC's from HIF-1α, permitting formation of the HIF-1 transcription complex, leading to downstream activation of target genes. Previously, under conditions mimicking hypoxia, cells treated with the hypoxic mimetic, deferoxamine, plus high-risk HPV E7 or E6 exhibited higher protein levels of HIF-1α in comparison to non-transduced keratinocytes under the same conditions (Nakamura et al., 2009). "
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    • "MTA1-interacting coactivator has been identified as a molecule that interacts with MTA1 to regulate estrogen receptor-α transactivation (18). Yoo et al(19) reported that MTA1 stabilizes hypoxia-inducible factor-1α protein by recruiting histone deacetylase 1, and is correlated with angiogenesis in cancer development (20). Since MTA1 is a histone deacetylase (HDAC)-interacting protein that modulates the epigenetic status of its target genes, it is expected to widely influence the expression pattern of the cancer-related gene spectrum. "
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