LncRNA HOTAIR contributes to cigarette smoke-induced pro-inflammatory responses in human airway epithelial cells

Inhalation of cigarette smoke (CS) is the primary risk factor for COPD, inducing epigenetic changes in the airway epithelium, including dysregulation of long-noncoding RNAs (lncRNAs). LncRNA HOTAIR (Homeobox gene Transcript Antisense RNA) regulates chromatin remodeling and has been implicated in CS-induced malignant transformation. We hypothesized that HOTAIR expression is altered in COPD, leading to airway epithelial abnormalities. HOTAIR expression and overall survival were studied in The Cancer Genome Atlas (TCGA) database. Airway epithelial cells (AECs) were isolated from transplanted lungs of 11 COPD patients, tracheobronchial tissue of 9 non-COPD donors and bronchial brushings of ex-smokers with/without COPD (n=6/group). HOTAIR expression, histone modifications and production of pro-inflammatory cytokines (CXCL8 and GM-CSF) were assessed in the absence/presence of CS extract (CSE) and HOTAIR-polycomb inhibitor AQB. High HOTAIR expression correlated with poor overall survival in cancer patients with COPD, but not those without. While HOTAIR expression was not significantly different between AECs from control and COPD subjects at baseline, it was significantly increased by 20% CSE only in COPD-derived AECs. CSE significantly decreased H3K4me3 levels in COPD-derived AECs, but not those from controls. AQB reduced baseline H3K27me3 levels in both groups, with a stronger effect in control-derived AECs. Additionally, it reduced H3K4me3 levels in the presence of CSE in both groups. Finally, while AQB significantly suppressed CSE-induced production of GM-CSF and CXCL8 in control AECs, it failed to do so in COPD. Together, these findings suggest that COPD-derived AECs are more susceptible to CSE-induced HOTAIR upregulation, which may have a pro-inflammatory effect that cannot be inhibited by AQB.