LKB1/PEA3/Delta Np63 pathway regulates PTGS-2 (COX-2) transcription in lung cancer cells upon cigarette smoke exposure

This is the first study to show that cigarette smoking induced the LKB1/PEA3/Delta Np63-dependent transcriptional regulation of inflammatory molecules, such as COX-2/PTGS-2. Using mainstream smoke extract (MSE) and sidestream smoke extract (SSE) as modeling toots for primary and secondhand smoking, we found that both MSE and SSE downregulated protein levels for LKB1, while upregulated protein levels for PEA3 and COX-2 in a dose-dependent manner. Using the endogenous ChIP analysis, we further found that the C/EBP beta, NF kappa B, NF-Y (CHOP), PEA3 (ETS) and Delta Np63 proteins bound to the specific area (-550 to -130) of the COX-2 promoter, while forming multiple protein complexes in lung cancer cells exposed to MSE and SSE. Our results define a novel link between various transcription factors occupying the COX-2 promoter and cellular response to cigarette smoke exposure bringing a new component, Delta Np63 alpha, showing a critical role for cooperation between various chromatin components in regulation of COX-2 expression and, therefore strengthening the central role of inflammatory process in tumorigenesis of epithelial cells, especially after cigarette smoke exposure (both primary and secondhand).