HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes.
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-β signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-β-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 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-β, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-β induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-β 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-β-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-β-induced Adam12 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-β. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-β and for the subsequent gene induction dependent on these signalling pathways.
Barter
Matt J
MJ
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Pybus
Leon
L
Litherland
Gary J
GJ
Rowan
Andrew D
AD
Clark
Ian M
IM
Edwards
Dylan R
DR
Cawston
Tim E
TE
Young
David A
DA
D051722:ADAM Proteins / Q000235:genetics; D000072199:ADAM12 Protein; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D058258:Serpin E2 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000099186:Histone Deacetylase 3
D051722:ADAM Proteins; D000072199:ADAM12 Protein; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019908:Proto-Oncogene Proteins c-raf; D034741:RNA, Small Interfering; D058258:Serpin E2; D051785:Smad Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D000099186:Histone Deacetylase 3; C511869:Serpine2 protein, mouse; C096115:Adam12 protein, mouse