Histone deacetylase 3 promotes alveolar epithelial–mesenchymal transition and fibroblast migration under hypoxic conditions

Abstract

Epithelial–mesenchymal transition (EMT), a process by which epithelial cells undergo a phenotypic conversion that leads to myofibroblast formation, plays a crucial role in the progression of idiopathic pulmonary fibrosis (IPF). Recently, it was revealed that hypoxia promotes alveolar EMT and that histone deacetylases (HDACs) are abnormally overexpressed in the lung tissues of IPF patients. In this study, we showed that HDAC3 regulated alveolar EMT markers via the AKT pathway during hypoxia and that inhibition of HDAC3 expression by small interfering RNA (siRNA) decreased the migration ability and invasiveness of diseased human lung fibroblasts. Furthermore, we found that HDAC3 enhanced the migratory and invasive properties of fibroblasts by positively affecting the EMT process, which in turn was affected by the increased and decreased levels of microRNA (miR)-224 and Forkhead Box A1 (FOXA1), respectively. Lastly, we found this mechanism to be valid in an in vivo system; HDAC3 siRNA administration inhibited bleomycin-induced pulmonary fibrosis in mice. Thus, it is reasonable to suggest that HDAC3 may accelerate pulmonary fibrosis progression under hypoxic conditions by enhancing EMT in alveolar cells through the regulation of miR-224 and FOXA1. This entire process, we believe, offers a novel therapeutic approach for pulmonary fibrosis.

Construction of a TFs-miRNA-mRNA network related to idiopathic pulmonary fibrosis

“…Another study reported that treatment with EZH2 inhibitors could suppress M1 macrophages while promoting M2 macrophage differentiation by activating peroxisome proliferator-activated receptor ( PPAR )-γ and modulating the signal transducer and activator of transcription/ suppressor of cytokine signaling ( STAT / SOCS ) pathway ( 61 ). MicroRNA-224 ( miR - 224 ) and its target forkhead box A1 ( FOXA1 ) inhibit the expression of EMT markers and the migration and invasion of human lung fibroblasts in IPF under hypoxia ( 62 ). Bromodomain containing 4 ( BRD4 ) plays a critical role in promoting pulmonary myofibroblast activation and redox imbalance, and BRD4 inhibitors is capable of inhibiting the profibrotic effects of IPF and attenuates bleomycin-induced lung fibrosis in mice ( 63 , 64 ).…”

Epigenetic Regulation of EMP/EMT-Dependent Fibrosis

“…HDAC3 significantly increased Snail expression under hypoxic conditions, and this effect was prevented by inhibition of Hypoxia-inducible factor 1-alpha (HIF1 α), a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 ( HIF-1 ). HDAC3 increases the transcriptional activity of HIF-1α by promoting the binding of HIF-1α to the hypoxia-responsive element (HRE) sites of genes [ 129 ]. Since fibroblast migration is considered a critical contributor to lung fibrosis, it was recently demonstrated that HDAC3-miR224- Forkhead Box A1 (FOXA1) axis effectively regulated the migration and invasion of fibroblast cells under hypoxia [ 129 ].…”

“…HDAC3 increases the transcriptional activity of HIF-1α by promoting the binding of HIF-1α to the hypoxia-responsive element (HRE) sites of genes [ 129 ]. Since fibroblast migration is considered a critical contributor to lung fibrosis, it was recently demonstrated that HDAC3-miR224- Forkhead Box A1 (FOXA1) axis effectively regulated the migration and invasion of fibroblast cells under hypoxia [ 129 ]. The effective involvement of HDAC3 in EMT-dependent fibrosis in lung was demonstrated by the use of HDAC3 siRNA that alleviated BLM-induced pulmonary fibrosis in mice.…”

“…The effective involvement of HDAC3 in EMT-dependent fibrosis in lung was demonstrated by the use of HDAC3 siRNA that alleviated BLM-induced pulmonary fibrosis in mice. In addition, FOXA1 gene was identified as the target gene of miR-224 in HDAC3-mediated alveolar EMT [ 129 ] and HDAC3 promotes hypoxia-induced alveolar EMT through stabilization of HIF-1α via the AKT pathway [ 129 ].…”

HDAC3 deficiency protects against acute lung injury by maintaining epithelial barrier integrity through preserving mitochondrial quality control

“…Similarly, pharmacologic inhibition of class I HDACs via SAHA or MS275 in the context of diabetes and obesity enhanced mitochondrial function as well as oxidative capacity in adipose tissue and skeletal muscle [ 24 ]. Under hypoxic conditions, HDAC3 accelerated the progression of pulmonary fibrosis by promoting epithelial-mesenchymal transition in alveolar epithelial cells [ 25 ]. However, it remains unknown whether HDAC3 deletion could attenuate LPS-induced ALI and epithelial barrier dysfunction by modulating MQC in alveolar epithelial cells.…”