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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with no effective treatment and an unclear pathogenesis [1]
To explore new drugs for IPF, we investigated the therapeutic potential of the histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA, Vorinostat, Merck)
We demonstrated that SAHA can downregulate type III collagen expression on transcriptional and translational levels; the downregulation is associated with specific histone modifications
Summary
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with no effective treatment and an unclear pathogenesis [1] It is characterized by distorted pulmonary structure accompanied by excessive deposition of extracellular matrix (ECM) proteins, such as collagen, and the presence of apoptosis-resistant myofibroblasts [2]. Others demonstrated that SAHA can abrogate the TGF-β effect on increasing collagen I deposition [10]; another HDAC inhibitor, trichostatin A, can inhibit collagen I mRNA induction by TGF-β in human lung fibroblasts [11]. The effects of SAHA on the increased collagen type III in IPF [12,13], as well as the associated changes of histone modifications with this gene (COL3A1) have not been explored. We examined if collagen III production can be inhibited by the SAHA treatment in a murine model of bleomycin-induced pulmonary fibrosis
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