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

Research output: Contribution to journalArticle

57 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

Research Output

  • 57 Citations
  • 10 Article
  • 3 Meeting Abstract

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Baker, J., Falconer, A., Wilkinson, D. J., Europe-Finner, G. N., Litherland, G. & Rowan, A. D., 13 Apr 2018, In : PLoS ONE. 13, 4, 19 p., e0195864.

Research output: Contribution to journalArticle

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    Chan, C. M., Macdonald, C. D., Litherland, G., Wilkinson, D. J., Skelton, A., Europe-Finner, G. N. & Rowan, A. D., 12 Dec 2016, In : Journal of Biological Chemistry.

    Research output: Contribution to journalArticle

    Open Access
  • 17 Citations (Scopus)

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    Rowan, A. D. & Litherland, G. J., Oct 2015, In : Biochemical Society Transactions. 43, p. 1051-1056

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Cite this

    Barter, M. J., Pybus, L., Litherland, G. J., Rowan, A. D., Clark, I. M., Edwards, D. R., Cawston, T. E., & Young, D. A. (2010). HDAC-mediated control of ERK- and PI3K-dependent TGF-beta-induced extracellular matrix-regulating genes. Matrix Biology, 29(7), 602-612. https://doi.org/10.1016/j.matbio.2010.05.002