Transcriptional induction of MMP-10 by TGF-beta, mediated by activation of MEF2A and downregulation of class IIa HDACs.
Transforming growth factor (TGF)-beta 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-beta in mammary epithelial cells and found that the induction was dependent on the myocyte enhancer factor (MEF)-2 transcription factor. TGF-beta 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-beta, 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-beta. 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-beta 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-beta and alleviated by overexpression of HDACs. Collectively, it is possible that TGF-beta 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.
Ishikawa
F
F
Department of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo, Japan.
Miyoshi
H
H
Nose
K
K
Shibanuma
M
M
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D064326:MEF2 Transcription Factors; D053506:Matrix Metalloproteinase 10 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D006657:Histones; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D016212:Transforming Growth Factor beta; D004247:DNA; D053506:Matrix Metalloproteinase 10; D056464:Histone Deacetylase 2