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

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. Lung fibrosis: Enzyme inhibition could limit disease progression Inhibiting an enzyme that boosts the invasiveness of fibrosis-related cells could prove to be a novel therapeutic strategy for treating idiopathic lung fibrosis. Lung fibrosis progresses via the transition of epithelial cells into myofibroblasts, which are migratory invasive cell types that secrete collagen and deposit excessive extracellular material. Low oxygen conditions (hypoxia) accelerate this transition process. Scientists recently identified a group of histone deacetylases (HDACs) that are significantly overexpressed in the lung tissues of patients with fibrosis. In experiments on mice and human cell lines, Jeong-Woong Park and Se-Hee Kim at Gachon University Gil Medical Center, Incheon, South Korea, and co-workers demonstrated that under hypoxic conditions, HDAC3 increases the cellular transition to myofibroblasts by regulating the expression of a key microRNA and its target gene. Inhibiting HDAC3 suppresses the migration and invasiveness of lung myofibroblasts.