Abstract
Cigarette smoke is a risk factor for COPD and lung cancer. In cancer, epigenetic modifications affect the expression of Enhancer of Zester Homolog 2 (EZH2), and silenced disabled homolog 2 interacting protein gene (DAB2IP) (onco-suppressor gene) by Histone H3 tri-methylation in lysine 27 (H3K27me3). In“ex vivo”studies, we assessed EZH2, H3K27me3 and DAB2IP immunoreactivity in bronchial epithelial cells from COPD patients (smokers, ex-smokers), Smoker and control subjects. In“in vitro” experiments we studied the effect of cigarette smoke extract (CSE) on EZH2/H3K27me3/DAB2IP expression, apoptosis, invasiveness, and vimentin expression in 16HBE, primary cells, and lung cancer cell lines (A549) long-term exposed to CSE. Finally, in “in vitro”studies, we tested the effect of GSK343 (selective inhibitor of EZH2). EZH2 and H3K27me3 expression was higher, while DAB2IP was lower levels, in bronchial epithelium from COPD and Smokers than in Controls. CSE increased EZH2, H3K27me3 expression and decreased DAB2IP, cell apoptosis and invasiveness in epithelial cells. GSK343 restored the effects of CSE. Cigarette smoke affects EZH2 expression, and reduced DAB2IP via H3K27me3 in COPD patients. The molecular mechanisms associated with EZH2 expression, generate a dysregulation of cell apoptosis, mesenchymal transition, and cell invasiveness in bronchial epithelial cells, encouraging the progression of airway inflammation toward lung cancer in COPD patients.
Highlights
90% of Chronic Obstructive Pulmonary Disease (COPD) are smokers or ex smokers[1]
Enhancer of zester homolog 2 (EZH2) immunoreactivity significantly increased in bronchial epithelium of COPD Smokers compared to Smokers subjects and to COPD ex-smokers (p < 0.001 and p < 0.001, respectively) and in COPD ex-smokers compared to Smokers (p < 0.04)
Our findings suggest that the altered EZH2/ H3K27me3/Disabled homolog 2-interacting protein (DAB2IP) expression observed in COPD patients could be cause of an irregular proliferation in epithelial cells, present in the area of the metaplasia, known to be a pre-neoplastic change in response to www.nature.com/scientificreports
Summary
90% of Chronic Obstructive Pulmonary Disease (COPD) are smokers or ex smokers[1]. the habit to cigarette smoke is major risk factor for COPD1. Enhancer of zester homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PCR2), and its-terminal SET domain exhibits methyl transferase activity[9] It plays an important role in epigenetic silencing of genes, by tri-methylation of Histone H3 in lysine 27 residue (H3K27me[3]). The aim of present study is to identify the connection between the habit to cigarette smoking, chronic inflammation and tumorigenic markers studying EZH2, DAB2IP expression and H3K27me[3] in an ex vivo/in vitro model of airway diseases. We first evaluated: (1)“ex vivo “ the EZH2, DAB2IP and H3K27me[3] immunoreactivity in bronchial epithelium from COPD patients (smokers and ex-smokers), Smokers and control subjects; we studied: (2)“in vitro”, the EZH2, DAB2IP andH3K27me[3] expression in epithelial cells (normal and cancer cell line or primary epithelial cells) chronically exposed to Cigarette Smoke Extract (CSE). We evaluated the effect of EZH2 over-expression on cell apoptosis, epithelial to mesenchymal transition, and cell invasiveness, of epithelial cells exposed to CSE for long time
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