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

Abstract

a b s t r a c t a r t i c l e i n f oHistone 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 semiselective 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.

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

“…HDAC3 is known to interact with HDAC5 (Fischle et al, 2002). HDAC3 has been shonw to mediate TGF-β-induced expression in C3H10T1/2 fibroblasts (Barter et al, 2010). Because decreased expression of HDAC3 occurred earlier than induction of PAI-1, we hypothesized that HDAC3 might exert a negative HUVECs were treated with or without HA (1 mDa, 200 µg/ml) for 1 h, after which the cell lysates were subjected to cytokine array analysis as described.…”

Association of histone acetylation at the ACTA2 promoter region with epithelial mesenchymal transition of lens epithelial cells

“…9,19 Alternatively, TSA might abrogate EMT by downregulating other pathways like Notch, MAPK, and PI3K pathways. 12,20 TSA is emerging as a strong therapeutic candidate for many inflammatory diseases as well as cancer. 32 Our results clearly suggest that epigenetic modifications are involved during myofibroblastic differentiation of LECs and TSA suppresses the main features of EMT induced by TGF-β, in terms of preserving the morphological features, reducing migratory capacity of cells, and inhibiting increased αSMA expression.…”

“…[9][10][11][12] Histone (de) acetylation is one such epigenetic mechanism that controls transcription. Opposing effects of histone acetyltransferases (HATs) and their counterpart histone deacetylases (HDACs) mediate histone acetylation.…”

“…The role of HDACs in mediating myofibroblast differentiation driven by TGF-β has been previously documented using different cell types. [10][11][12]14 Several HDAC inhibitors (HDACis) have been developed that block the catalytic reaction of HDAC, leading to hyperacetylation of histones. Trichostatin-A (TSA), an HDACi, is a fermentation product derived from streptomyces species and is a potent and specific inhibitor of HDACs.…”

Valproate activates ERK signaling pathway in primary human hepatocytes

“…Interestingly, it has been proposed that VPA activates pERK2 through attenuation of the PKA signalling pathway and this might be the common mechanism for VPA and lithium in the treatment of bipolar disorder 23 . In addition, although some reports suggest that HDAC inhibition mediated by VPA causes ERK pathway activation, there are also contradictory data observed in other tissues 16,24,25 .…”