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- Title
Transcriptional induction of MMP-10 by TGF-β, mediated by activation of MEF2A and downregulation of class IIa HDACs.
- Authors
Ishikawa, F.; Miyoshi, H.; Nose, K.; Shibanuma, M.
- 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.
- Subjects
TRANSFORMING growth factors; METALLOPROTEINASES; MUSCLE cells; HISTONES; ACETYLATION
- Publication
Oncogene, 2010, Vol 29, Issue 6, p909
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2009.387