Smoking Induces Epithelial-to-Mesenchymal Transition in Non-Small Cell Lung Cancer through HDAC-Mediated Downregulation of E-cadherin
Menée sur des lignées cellulaires et 310 échantillons tumoraux prélevés sur des patients atteints d'un cancer du poumon non à petites cellules, cette étude met en évidence un mécanisme par lequel, en régulant l'expression de l'E-cadhérine, la fumée de cigarettes induit une transition épithélio-mésenchymateuse
Epidemiological studies have demonstrated that most cases of lung cancers (85-90%) are directly attributable to tobacco smoking. Although association between cigarette smoking and lung cancer is well documented, surprisingly little is known regarding the molecular mechanisms of how smoking is involved in epithelial-to-mesenchymal transition (EMT) through epigenetic changes. Here we show that lung cancer patients with a smoking history have low E-cadherin (E-cadh) levels and loss of E-cadh is a poor prognostic factor in smokers. Moreover, the downregulation of E-cadh correlates with the number of pack-years. In an attempt to determine the role of long-term cigarette smoking on EMT, we have observed that treatment of lung cell lines with cigarette smoke condensate (CSC) induces EMT through downregulation of epithelial markers including E-cadh and upregulation of mesenchymal markers. CSC decreases E-cadh expression at the transcriptional level through upregulation of LEF1 and Slug, and knockdown of these two proteins increases E-cadh expression. Importantly, chromatin immunoprecipitation assays suggest that LEF-1 and Slug binding to E-cadh promoter is important for CSC-mediated downregulation of E-cadh. The histone deacetylase inhibitor (HDACi) MS-275 reverses CSC-induced EMT, migration and invasion through the restoration of E-cadh expression. These results suggest that recruitment of HDACs by transcriptional repressors, LEF-1 and Slug is responsible for E-cadh suppression and EMT in cigarette smokers and provide a potential drug target towards the treatment of lung cancer.
http://mct.aacrjournals.org/content/early/2012/08/29/1535-7163.MCT-12-0107.abstract