Trichostatin A blocks TGF-β-induced collagen gene expression in skin fibroblasts: Involvement of Sp1

• Published in: Biochemical and biophysical research communications 2007-03, Vol.354 (2), p.420-426
• Main Authors: Ghosh, Asish K., Mori, Yasuji, Dowling, Elizabeth, Varga, John
• Format: Article
• Language: English
• Subjects: Cells, Cultured; Collagen - antagonists & inhibitors; Collagen - biosynthesis; Collagen - genetics; Fibroblasts; Fibroblasts - drug effects; Fibrosis; Gene Expression Regulation - drug effects; Histone acetyltransferase; Histone deacetylase; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids - pharmacology; Smad; Sp1; Sp1 Transcription Factor - physiology; TGF-β; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - physiology; Trichostatin A; Type I collagen
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2006.12.204

Transforming growth factor- β (TGF-β) stimulates Type I collagen synthesis by fibroblasts and is implicated in tissue fibrosis. Here, we demonstrate that histone deacetylase inhibitor Trichostatin A (TSA) suppresses the TGF-β-induced Type I collagen synthesis but not induced PAI-1 synthesis suggesting the influence of TSA is gene specific. Results further reveal that there is no significant alteration in Smad activation and function in presence of TSA suggesting suppression of TGF-β-induced collagen synthesis is not due to impaired Smad signaling. TGF-β induces the levels of Sp1, an essential transcription factor of Smad-dependent stimulation of collagen synthesis. However, in presence of TSA, TGF-β fails to induce Sp1 levels, its interaction with Smad complex and Sp1 binding site in COL1A2 promoter. Furthermore, overexpressed Sp1 reverses the TSA-mediated inhibition of TGF-β-induced collagen gene expression. Collectively, these results suggest that TSA-mediated suppression of Smad-dependent TGF-β-induced collagen synthesis is due to suppression of Sp1 activity in skin fibroblasts.