HDAC-mediated control of ERK- and PI3K-dependent TGF-beta-induced extracellular matrix-regulating genes

Matt J. Barter, Leon Pybus, Gary J. Litherland, Andrew D. Rowan, Ian M. Clark, Dylan R. Edwards, Tim E. Cawston, David A. Young

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56 Citations (Scopus)

Abstract

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-beta signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-beta-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam 12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-beta. whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-beta induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-beta induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-beta-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-beta-induced Adam 12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-beta. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-beta and for the subsequent gene induction dependent on these signalling pathways.
Original languageEnglish
Pages (from-to)602-612
JournalMatrix Biology
Volume29
Issue number7
DOIs
Publication statusPublished - Sep 2010
Externally publishedYes

Keywords

  • Histone deacetylases
  • HDAC3
  • TGF-beta
  • Signalling
  • ERK
  • PI3K
  • ADAM12
  • TIMP-1

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