Cigarette smoke alters the EZH2/DAB2IP expression in bronchial epithelial cells. A risk factor for lung cancer in COPD patients

Cigarette smoke is an environmental risk factor for COPD and Lung cancer, leading causes of morbidity and mortality worldwide. In cancer, enhancer of zeste homolog 2 (EZH2) silenced disabled homolog 2 interacting protein gene (DAB2IP) (tumor-suppressor gene) bytri-methylation of lysine 27 on histone H3 (H3K27me3). We studied EZH2 and DAB2IP expression in airway epithelial cells from COPD patients and their potential involvement in the progression of COPD toward lung cancer. We assessed EZH2 and DAB2IPimmunoreactivity in bronchial epithelial cells from surgical specimens of COPD patients and healthy control subjects (HC) by immunohistochemistry. Bronchial epithelial cell line (16HBE), primary human bronchial epithelial cells (pHBE), lung cancer cell line (A549 and H292) were long term exposed to cigarette smoke extract (CSE) to study EZH2, DAB2IP and H3K27me3 expression and cell apoptosis. GSK343 (a selective inhibitor of EZH2) effect was tested on DAB2IP and H3K27me3 expression as well on cell apoptosis. DAB2IP immunoreactivity was significantly lower while EZH2 immunoreactivity was significantly higher in bronchial epithelium (positive cells/mm2) from COPD patients compared to bronchial epithelium from HC subjects. CSE treatment decreased DAB2IP while increased EZH2 and H3K27me3expression in 16HBE, pHBE, A549 and H292. Furthermore, GSK343 increased DAB2IP expression and cell apoptosis while decreased H3K27me3 in 16HBE, pHBE, A549 and H292 treated with CSE. Smoking habits generate a DAB2IP/EZH2 genes imbalance by H3K27me3 in bronchial epithelial cells from COPD patients, promoting defects in the apoptosis mechanism implicated in lung cancerogenesis.