HDAC8 inhibition ameliorates pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disease with high mortality, and fibroblast‐myofibroblast differentiation (FMD) is thought to be a key event in the pathogenesis of IPF. Histone deacetylase 8 (HDAC8) has been shown to associate with α‐smooth muscle actin (α‐SMA; a marker of FMD) and regulates cell contractility in vascular smooth muscle cells. However, the role of HDAC8 in FMD or pulmonary fibrosis has never been investigated. This study investigated the role of HDAC8 in pulmonary fibrosis, with a focus on FMD. We observed that HDAC8 expression was increased in IPF lung tissue as well as TGF‐β1‐treated normal human lung fibroblasts (NHLFs). Our immunoprecipitation experiments revealed that HDAC8 associated with α‐SMA in TGF‐β1‐treated NHLFs. HDAC8 inhibition with NCC170 (HDAC8‐ selective inhibitor) repressed TGF‐β1‐induced fibroblast contraction and α‐SMA protein expression in NHLFs cultured in collagen gels. HDAC8 inhibition with HDAC8 siRNA also repressed TGF‐β1‐induced expression of CTGF and PAI‐1, and increased PPAR‐γ expression in NHLFs. Chromatin immunoprecipitation quantitative PCR (ChIP‐qPCR) using an antibody against H3K27ac (histone H3 acetylated at lysine 27; a known HDAC8 substrate and a marker for active enhancers) suggested that HDAC8 inhibition with NCC170 ameliorated TGF‐β1‐ induced loss of H3K27ac at the PPAR‐γ gene enhancer. Furthermore, NCC170 treatment significantly decreased fibrosis measured by Ashcroft score as well as type‐1 collagen expression in bleomycin‐treated mouse lungs. In conclusion, these data suggest that HDAC8 contributes to pulmonary fibrosis and that there is a therapeutic potential for HDAC8 inhibitors to treat IPF as well as other fibrotic lung diseases. Support or Funding Information Wetmore Foundation: Shigeki Saito M1: 555007G1; Louisiana Clinical and Translational Science (LA CaTS) Center: Shigeki Saito 1 U54 GM104940 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

“…Interestingly, we found that knockdown of HDAC7 in the presence of TGFβ also modestly reduced expression of HDAC8 (Fig. S1C), which has previously been shown to drive fibroblast activation in vitro and in vivo (Saito et al, 2019), suggesting an additional target through which HDAC7 may regulate fibroblast activation. HDAC7 knockdown strongly attenuated TGFβ upregulation of fibrosis-associated genes (ACTA2, NOX4 and CTGF) ( Fig.…”

Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis

“…HDAC8 has emerged as an attractive target for isotype‐selective drug development in a variety of diseases, such as cancer, parasitic, and viral infections, as well as neurodegenerative diseases 18 . Despite selective inhibition of HDAC8 with NCC170 has been shown to offer a beneficial effect to pulmonary fibrosis in an animal model of idiopathic pulmonary fibrosis, 45 the role of this enzyme and efficacy of HDAC8 selective inhibitors in other models of diseases associated with tissue fibrosis remain largely unknown. In this work, we demonstrated a remarkable inhibitory effect of PCI34051 on HDAC8, EMT, and renal fibrosis.…”

Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor

“…It has been reported that pharmacological inhibition of HDACs led to the activation of the peroxisome proliferator-activated receptor (PPAR)γ, a member of nuclear receptors associated with lipogenesis and cell metabolism [18]. In addition, the HDAC8 inhibitor NCC170 was shown to ameliorate idiopathic pulmonary fibrosis, in part, by increasing PPARγ expression [19]. Here, the effect of HMC on PPARγ was assessed using an established PPRE-luciferase reporter assay in MCF7-cells [20].…”