LKB1/PEA3/ΔNp63 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/ΔNp63-dependent transcriptional regulation of inflammatory molecules, such as COX-2/PTGS-2. Using mainstream smoke extract (MSE) and sidestream smoke extract (SSE) as modeling tools for primary and second-hand smoking, we found that both MSE and SSE down regulated protein levels for LKB1, while up regulated protein levels for PEA3 and COX-2 in a dose-dependent manner. Using the endogenous ChIP analysis, we further found that the C/EBPβ, NF-kB, NF-Y (CHOP), PEA3 (ETS), and ΔNp63 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, ΔNp63α, 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 second-hand.