Cigarette smoking (CS), a major risk factor for COPD and lung cancer (LC). It induces epigenetic changes in the airway epithelium, affecting genes involved in epithelial repair and remodelling (e.g. P21 and CDH1). Transcription factor MEOX2 has been implicated in abnormal epithelial repair in LC, regulating chromatin remodelling. Abnormal epithelial repair is also observed in COPD, and we hypothesize that MEOX2 forms a molecular link between COPD and LC.

To identify MEOX2 targets, ChIP-seq was performed in lung carcinoma A549 cells. RNA-seq data were analysed in the TCGA cohort of LC patients with/without COPD (FEV1/FVC<0.7/FEV1/FVC?0.7). Primary airway epithelial cells (AECs) were derived from healthy and COPD donors (n=3-6/group). MEOX2 was downregulated by siRNA. Effects on epigenetic marks H3K27me3/H3K4me3 and gene expression of CDH1 and P21 were assessed in presence/absence of CS extract (CSE). Metabolic activity was analysed in A549 (MTS assay).

ChIP-seq GSEA analysis indicated that MEOX2 regulates genes involved in cell-cycle progression and migration. RNA-seq data showed that MEOX2 correlates positively with P21 and negatively with CDH1, only in COPD-LC patients. CSE exposure tended to increase expression of MEOX2, H3K27me3 and P21, while MEOX2 downregulation decreased P21 and H3K27me3 and increased CDH1 expression in AECs. siMEOX2 significantly increased A549 metabolic activity upon CSE exposure.

Together, our results suggest that CS induces MEOX2 expression in lung epithelial cells, which may subsequently increase in H3K27me3 abundance, inducing P21 and reducing CDH1 expression, potentially contributing to abnormal epithelial repair in COPD and LC.