Histone deacetylase 3 deletion in alveolar type 2 epithelial cells prevents bleomycin-induced pulmonary fibrosis

Clin Epigenetics. 2023 Nov 11;15(1):182. doi: 10.1186/s13148-023-01588-5.

Abstract

Background: Epithelial mesenchymal transformation (EMT) in alveolar type 2 epithelial cells (AT2) is closely associated with pulmonary fibrosis (PF). Histone deacetylase 3 (HDAC3) is an important enzyme that regulates protein stability by modulating the acetylation level of non-histones. Here, we aimed to explore the potential role and regulatory mechanisms associated with HDAC3 in PF.

Methods: We quantified HDAC3 expression both in lung tissues from patients with PF and from bleomycin (BLM)-treated mice. HDAC3 was also detected in TGF-β1-treated AT2. The mechanistic activity of HDAC3 in pulmonary fibrosis and EMT was also explored.

Results: HDAC3 was highly expressed in lung tissues from patients with PF and bleomycin (BLM)-treated mice, especially in AT2. Lung tissues from AT2-specific HDAC3-deficient mice stimulated with BLM showed alleviative fibrosis and EMT. Upstream of HDAC3, TGF-β1/SMAD3 directly promoted HDAC3 transcription. Downstream of HDAC3, we also found that genetic or pharmacologic inhibition of HDAC3 inhibited GATA3 expression at the protein level rather than mRNA. Finally, we found that intraperitoneal administration of RGFP966, a selective inhibitor of HDAC3, could prevent mice from BLM-induced pulmonary fibrosis and EMT.

Conclusion: TGF-β1/SMAD3 directly promoted the transcription of HDAC3, which aggravated EMT in AT2 and pulmonary fibrosis in mice via deacetylation of GATA3 and inhibition of its degradation. Our results suggest that targeting HDAC3 in AT2 may provide a new therapeutic target for the prevention of PF.

Keywords: Acetylation; EMT; GATA3; HDAC3; PF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / metabolism
  • Bleomycin / pharmacology
  • DNA Methylation
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition
  • Humans
  • Lung / metabolism
  • Mice
  • Pulmonary Fibrosis* / chemically induced
  • Pulmonary Fibrosis* / genetics
  • Pulmonary Fibrosis* / prevention & control
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Transforming Growth Factor beta1
  • Bleomycin
  • histone deacetylase 3