Histone deacetylase inhibition downregulates collagen 3A1 in fibrotic lung fibroblasts.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by chronic inflammation and excessive collagen accumulation in the lung. Myofibroblasts are the primary collagen-producing cells in pulmonary fibrosis. Histone deacetylase inhibitor (HDACi) can affect gene expression, and some, such as suberoylanilide hydroxamic acid (SAHA), are US FDA approved for cancer treatment. In this study, we investigated SAHA's effects on the expression of collagen III alpha 1 (COL3A1) in primary human IPF fibroblasts and in a murine model of pulmonary fibrosis. We observed that increased COL3A1 expression in IPF fibroblasts can be substantially reduced by SAHA treatment at the level of transcription as detected by RT-PCR; collagen III protein level was also reduced, as detected by Western blots and immunofluorescence. The deacetylation inhibitor effect of SAHA was verified by observing higher acetylation levels of both histone H3 and H4 in treated IPF cells. Chromatin immunoprecipitation (ChIP) experiments demonstrated that the reduced expression of COL3A1 by SAHA is with increased association of the repressive chromatin marker, H3K27Me3, and decreased association of the active chromatin marker, H3K9Ac. In our murine model of bleomycin-induced pulmonary fibrosis, the SAHA treated group demonstrated significantly less collagen III, as detected by immunohistochemistry. Our data indicate that the HDACi SAHA alters the chromatin associated with COL3A1, resulting in its decreased expression.

• Authors: Xiangyu Zhang, Hui Liu, Thomas Hock, Victor J Thannickal, Yan Y Sanders
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 14 Issue 10 Pg. 19605-17 (Sep 27 2013) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 24084714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COL3A1 protein, human
• Chromatin
• Collagen Type III
• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• Vorinostat
• Histone Deacetylases

Topics

• Animals
• Cells, Cultured
• Chromatin (genetics, metabolism)
• Collagen Type III (genetics, metabolism)
• Down-Regulation (genetics)
• Fibroblasts (drug effects, metabolism)
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (genetics, metabolism)
• Histones (genetics, metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Idiopathic Pulmonary Fibrosis (genetics, metabolism)
• Lung (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Pulmonary Fibrosis (genetics, metabolism)
• Vorinostat