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

Asish K. Ghosh; Yasuji Mori; Elizabeth Dowling; John Varga

doi:10.1016/j.bbrc.2006.12.204

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

Asish K. Ghosh^*, Yasuji Mori, Elizabeth Dowling, John Varga

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

87 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	420-426
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	354
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2006.12.204
State	Published - Mar 9 2007

Keywords

Fibroblasts
Fibrosis
Histone acetyltransferase
Histone deacetylase
Smad
Sp1
TGF-β
Trichostatin A
Type I collagen

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.bbrc.2006.12.204

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

abstract = "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.",

keywords = "Fibroblasts, Fibrosis, Histone acetyltransferase, Histone deacetylase, Smad, Sp1, TGF-β, Trichostatin A, Type I collagen",

author = "Ghosh, {Asish K.} and Yasuji Mori and Elizabeth Dowling and John Varga",

note = "Funding Information: This work was supported by grants from Scleroderma Foundation (to A.K.G.) and NIH (AR-42309 to J.V.). We are grateful to Drs. N. Shane Cutler (University of Utah, Salt Lake City, UT), Kohei Miyazono (Cancer Institute, Tokyo, Japan), Bert Vogelstein (Johns Hopkins University, Baltimore, MD), and Joan Massague (Howard Hughes Medical Institute, New York, NY), for providing plasmids.",

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doi = "10.1016/j.bbrc.2006.12.204",

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T1 - Trichostatin A blocks TGF-β-induced collagen gene expression in skin fibroblasts

T2 - Involvement of Sp1

AU - Ghosh, Asish K.

AU - Mori, Yasuji

AU - Dowling, Elizabeth

AU - Varga, John

N1 - Funding Information: This work was supported by grants from Scleroderma Foundation (to A.K.G.) and NIH (AR-42309 to J.V.). We are grateful to Drs. N. Shane Cutler (University of Utah, Salt Lake City, UT), Kohei Miyazono (Cancer Institute, Tokyo, Japan), Bert Vogelstein (Johns Hopkins University, Baltimore, MD), and Joan Massague (Howard Hughes Medical Institute, New York, NY), for providing plasmids.

PY - 2007/3/9

Y1 - 2007/3/9

N2 - 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.

AB - 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.

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KW - Fibrosis

KW - Histone acetyltransferase

KW - Histone deacetylase

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KW - Trichostatin A

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

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