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Transcriptional induction of MMP-10 by TGF-β, mediated by activation of MEF2A and downregulation of class IIa HDACs

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Abstract

Transforming growth factor (TGF)-β regulates the expression of matrix metalloproteinases (MMPs) and components of the extracellular matrix, thereby profoundly affecting the microenvironment of cells including cancerous ones. We studied MMP-10 induction by TGF-β in mammary epithelial cells and found that the induction was dependent on the myocyte enhancer factor (MEF)-2 transcription factor. TGF-β upregulated the gene promoter through the MEF2 site, and knockdown of the MEF2A transcription factor negatively affected MMP-10 induction, whereas its overexpression had a positive effect on the induction. In response to TGF-β, acetylation and concomitant binding of MEF2A to the promoter region increased, thus suggesting a critical role of MEF2A in transactivation of MMP-10 by TGF-β. Consistent with the fact that class IIa histone deacetylases (HDACs) interact with MEF2 and suppress transcription, knockdown of HDACs increased and their overexpression inhibited MMP-10 expression. Intriguingly, TGF-β promoted proteasome-dependent degradation of HDACs. Consistent with this, acetylation of core histones was increased around the MEF2 site of the MMP-10 promoter by TGF-β and alleviated by overexpression of HDACs. Collectively, it is possible that TGF-β transcriptionally upregulated MMP-10 through activation of MEF2A, concomitant with acetylation of core histones increasing around the promoter, as a consequence of degradation of the class IIa HDACs.

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Acknowledgements

We thank Dr Eric N Olson (University of Texas Southwestern Medical School, Dallas, TX, USA) for his generous gift of the MMP-10 promoter luciferase constructs. We also thank Ms E Kaneko and Ms T Kaneko for contributing to this work as a project for their bachelor's degree. This work was supported in part by a Grant-in-Aid for Scientific Research (C) (19570185) and the High-Technology Research Center Project from the Ministry for Education, Culture Sports, Science and Technology (MEXT) of Japan, and also by the High-Tech Research Centre Project for Private Universities: a matching fund subsidy from MEXT, 2007–2009.

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Authors and Affiliations

  1. Department of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo, Japan

    F Ishikawa, K Nose & M Shibanuma

  2. Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Koyadai, Tsukuba, Ibaraki, Japan

    H Miyoshi

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  1. F Ishikawa
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  2. H Miyoshi
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Correspondence to M Shibanuma.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Ishikawa, F., Miyoshi, H., Nose, K. et al. Transcriptional induction of MMP-10 by TGF-β, mediated by activation of MEF2A and downregulation of class IIa HDACs. Oncogene 29, 909–919 (2010). https://doi.org/10.1038/onc.2009.387

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