Histone Deacetylases Promote ER Stress Induced Epithelial Mesenchymal Transition in Human Lung Epithelial Cells

Abstract

Background/Aims: Epithelial to mesenchymal transition (EMT) is a crucial process involved in pulmonary fibrosis. This study aimed to explore the role of histone deacetylases (HDACs) and endoplasmic reticulum (ER) stress in EMT in human lung epithelial cells. Methods: Human lung adenocarcinoma A549 cells were treated with bleomycin and tunicamycin to induce EMT. The proliferation of A549 cells was detected by MTT assay. The expression of HDACs and EMT markers was detected by PCR and Western blot analysis. The secretion of TGF-β1 and collagen I was examined by ELISA. Results: A549 cells switched from a cobblestone-like appearance to an elongated fibroblast like appearance after exposure to tunicamycin or bleomycin, accompanied by increased expression of N-cadherin, α-SMA and Collagen I. Meanwhile, GRP78 was upregulated in A549 cells exposed to tunicamycin or bleomycin. These changes induced by tunicamycin or bleomycin could be abrogated by 4-PBA. Moreover, tunicamycin and bleomycin promoted the expression of HDAC2 and HDAC6, and HDACs inhibitor SAHA abrogated the morphological and biochemical changes in A549 cells. 4-PBA and SAHA inhibited the upregulation of pulmonary fibrosis factors TGF-β1 and IL-32 and the activation of Smad pathway induced by tunicamycin or bleomycin. Conclusions: We provide the first evidence that tunicamycin and bleomycin induce ER stress and EMT in lung epithelial cells via the upregulation of HDACs. HDACs inhibitor could inhibit ER stress induced upregulation of pulmonary fibrosis factors and the activation of Smad pathway. HDACs inhibitors are promising agents for the therapy of pulmonary fibrosis.

IL-32 Induces Epithelial-mesenchymal Transition in Human Pulmonary Alveolar Epithelial Cells by Triggering Endoplasmic Reticulum Stress

“…Based on our previous study showing that TM can induce EMT in A549 cells, the cells were treated with 0.5 μg/ml TM for 24h [11]. Observation of the cells under an inverted microscope showed that the TM treatment induced significant cell death in a portion of the cells, with a lower cell number compared with that of the control group.…”

“…In addition, 4-phenylbutyric acid (4-PBA) was shown to inhibit the activation of ER stress and induction of EMT in AEC II cells [8][9][10]. We also previously reported that bleomycin and tunicamycin (TM) could induce ER stress and consequently trigger EMT through activation of histone deacetylase with accompanying interleukin (IL)-32 overexpression [11].…”

Endogenous Anti-Cancer Candidates in GPCR, ER Stress, and EMT

“…ER stress-inducing agents such as tunicamycin and bleomycin induced ER stress and EMT in lung epithelial cells via the up-regulation of HDACs. Inhibition of HDACs attenuated ER stress and the activation of Smad pathway of EMT induction since tunicamycin and bleomycin, the inducers of ER stress were reported to induce EMT in lung epithelial cells via the upregulation of HDACs [ 31 ].…”

TGF-β-Induced α-SMA Expression is Mediated by C/EBPβ Acetylation in Human Alveolar Epithelial Cells In Vitro

“…Although the precise mechanism underlying the pathogenesis of lung brosis is unclear, accelerated proliferation of myo broblasts has been shown to be possibly responsible for the excessive accumulation of ECM in the alveolar and interstitial compartments of the lung coupled with the development and prognosis of IPF [3,4]. Previous studies have reported that epithelial-to-mesenchymal transition (EMT) due to injuries to alveolar epithelial cells (AECs) could contribute considerably to the initiation and maintenance of brosis [5,6]. During the EMT process, the epithelial cells lose cellular interaction and gain mesenchymal phenotype as well as the ability to generate ECM.…”