Suberanilohydroxamic acid prevents TGF-?1-induced COX-2 repression in human lung fibroblasts post-transcriptionally by TIA-1 downregulation

Pasini, Alice; Brand, Oliver J.; Jenkins, Gisli; Knox, Alan J.; Pang, Linhua

Abstract

Cyclooxygenase-2 (COX-2), with its main antifibrotic metabolite PGE, is regarded as an antifibrotic gene. Repressed COX-2 expression and deficient PGE have been shown to contribute to the activation of lung fibroblasts and excessive deposition of collagen in pulmonary fibrosis. We have previously demonstrated that COX-2 expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) is epigenetically silenced and can be restored by epigenetic inhibitors. This study aimed to investigate whether COX-2 downregulation induced by the profibrotic cytokine transforming growth factor-?1 (TGF-?1) in normal lung fibroblasts could be prevented by epigenetic inhibitors. We found that COX-2 protein expression and PGE production were markedly reduced by TGF-?1 and this was prevented by the pan-histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) and to a lesser extent by the DNA demethylating agent Decitabine (DAC), but not by the G9a histone methyltransferase (HMT) inhibitor BIX01294 or the EZH2 HMT inhibitor 3-deazaneplanocin A (DZNep). However, chromatin immunoprecipitation assay revealed that the effect of SAHA was unlikely mediated by histone modifications. Instead 3'-untranslated region (3'-UTR) luciferase reporter assay indicated the involvement of post-transcriptional mechanisms. This was supported by the downregulation by SAHA of the 3'-UTR mRNA binding protein TIA-1 (T-cell intracellular antigen-1), a negative regulator of COX-2 translation. Furthermore, TIA-1 knockdown by siRNA mimicked the effect of SAHA on COX-2 expression. These findings suggest SAHA can prevent TGF-?1-induced COX-2 repression in lung fibroblasts post-transcriptionally through a novel TIA-1-dependent mechanism and provide new insights into the mechanisms underlying its potential antifibrotic activity.

Citation

Pasini, A., Brand, O. J., Jenkins, G., Knox, A. J., & Pang, L. (2018). Suberanilohydroxamic acid prevents TGF-?1-induced COX-2 repression in human lung fibroblasts post-transcriptionally by TIA-1 downregulation. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1861(5), https://doi.org/10.1016/j.bbagrm.2018.03.007

• Journal Article Type: Article
• Acceptance Date: Mar 14, 2018
• Online Publication Date: Mar 17, 2018
• Publication Date: May 30, 2018
• Deposit Date: May 11, 2018
• Publicly Available Date: May 11, 2018
• Journal: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
• Print ISSN: 1388-1981
• Electronic ISSN: 0006-3002
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 1861
• Issue: 5
• DOI: https://doi.org/10.1016/j.bbagrm.2018.03.007
• Keywords: Pulmonary fibrosis ; Cyclooxygenase 2 (COX-2) ; Post-transcriptional regulation ; epigenetics ; Histone deacetylase inhibitor ; Transforming growth factor ?1 (TGF-?1)
• Public URL: https://nottingham-repository.worktribe.com/output/934721
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1874939917303383