Histone deacetylase 4 is required for TGF beta 1-induced myofibroblastic differentiation

[en] Transforming Growth Factor beta 1 (TGF beta 1) is a crucial cytokine triggering myofibroblastic (MF) differentiation, a process involved in tissue healing as well as in pathologic conditions such as fibrosis and cancer. Together with cell shape modifications, TGF beta 1-mediated differentiation of fibroblasts into myofibroblasts is characteristically associated with the neo-expression of smooth muscle alpha-actin (alpha-SMA), a cytoskeletal protein that enhances their contractile activity. Several cellular differentiation programs have been linked to epigenetic regulation of gene expression, including gene methylation and historic acetylation. Herein, we sought to investigate the role of histone deacetylases (HDAC) in TGF beta 1-induced MY differentiation. We found that TSA, a global inhibitor of class I and class II HDACs, prevented alpha-SMA transcript and protein expression and morphological changes mediated by TGF beta 1 in cultured human skin fibroblasts. In order to identify the HDAC(s) participating in MF differentiation, the impact of specific HDAC silencing (HDAC1 through HDAC8) using RNA interference was investigated in fibroblasts exposed to TGF beta 1. Among the eight HDACs tested, silencing of HDAC4, HDAC6, and HDAC8 expression impaired TGF beta 1-induced alpha-SMA expression. HDAC4 silencing most efficiently abrogated alpha-SMA expression and also prevented TGF beta 1-mediated morphological changes. Forced down-regulation of HDAC4 stimulated the expression of 5'-TG-3'-Interacting Factor (TGIF) and TGIF2 homeoproteins, two known endogenous repressors of the TGF beta signaling pathway, but not of the inhibitory Smad7. Collectively, these data suggest that HDAC4 is an essential epigenetic regulator of MF differentiation and unveil HDAC4 as a potential target for treating MF-related disorders. (C) 2007 Published by Elsevier B.V.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Glenisson, Wendy

Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire

Waltregny, David ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Labo de recherche sur les métastases

Language :

English

Title :

Histone deacetylase 4 is required for TGF beta 1-induced myofibroblastic differentiation

Publication date :

October 2007

Journal title :

Biochimica et Biophysica Acta. Molecular Cell Research

ISSN :

0167-4889

eISSN :

1879-2596

Publisher :

Elsevier Science Bv, Amsterdam, Netherlands

Volume :

1773

Issue :

Pages :

1572-1582

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 25 January 2009

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145

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142

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