Journal Article

Targeting Histone Deacetylases in Idiopathic Pulmonary Fibrosis: A Future Therapeutic Option

Guenther, Andreas, Mahavadi, Poornima, Korfei, Martina

2022

Overview

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options, and there is a huge unmet need for new therapies. A growing body of evidence suggests that the histone deacetylase (HDAC) family of transcriptional corepressors has emerged as crucial mediators of IPF pathogenesis. HDACs deacetylate histones and result in chromatin condensation and epigenetic repression of gene transcription. HDACs also catalyse the deacetylation of many non-histone proteins, including transcription factors, thus also leading to changes in the transcriptome and cellular signalling. Increased HDAC expression is associated with cell proliferation, cell growth and anti-apoptosis and is, thus, a salient feature of many cancers. In IPF, induction and abnormal upregulation of Class I and Class II HDAC enzymes in myofibroblast foci, as well as aberrant bronchiolar epithelium, is an eminent observation, whereas type-II alveolar epithelial cells (AECII) of IPF lungs indicate a significant depletion of many HDACs. We thus suggest that the significant imbalance of HDAC activity in IPF lungs, with a “cancer-like” increase in fibroblastic and bronchial cells versus a lack in AECII, promotes and perpetuates fibrosis. This review focuses on the mechanisms by which Class I and Class II HDACs mediate fibrogenesis and on the mechanisms by which various HDAC inhibitors reverse the deregulated epigenetic responses in IPF, supporting HDAC inhibition as promising IPF therapy.

• Publisher: MDPI AG,MDPI
• Subject: Alveoli / Apoptosis / Cell proliferation / Chromatin / Deacetylation / Epigenetics / Epithelial cells / Epithelium / fibroblast-to-myofibroblast differentiation (FMD) / Fibroblasts / Fibroblasts - metabolism / Fibrosis / Gene silencing / Genes / Growth factors / histone acetylation / Histone deacetylase / histone deacetylase (HDAC) / Histone Deacetylase Inhibitors - pharmacology / Histone Deacetylase Inhibitors - therapeutic use / Histone Deacetylases - metabolism / Histones - metabolism / Humans / idiopathic pulmonary fibrosis (IPF) / Idiopathic Pulmonary Fibrosis - pathology / Kinases / Lung cancer / Lung diseases / Medical prognosis / Mortality / Mutation / non-histone protein acetylation / Polymorphism / Proteins / Pulmonary fibrosis / Review / Telomerase / Transcription factors / Transcription Factors - metabolism / Transcriptomes / Transgenic animals / Tumor necrosis factor-TNF / type-II alveolar epithelial cell (AECII)