SMAD4 promotes the EMT during cigarette smoke-induced airway remodeling in COPD by interacting with O-GlcNAc transferase

SMAD4 promotes the EMT during cigarette smoke-induced airway remodeling in COPD by interacting with O-GlcNAc transferase Cigarette smoke (CS), one prevalent chemical indoor air contaminant, is a leading cause of EMT during airway remodeling in COPD. Nevertheless, the potential mechanism by which SMAD4 mediates the development of COPD in CS-induced EMT remains elusive. In the present investigation, the SMAD4 expression was markedly increased in COPD patients, as well as in vitro along with in vivo models of COPD compared with controls. Functionally, down-regulation of SMAD4 attenuates EMT in CS-induced experimental COPD. Similarly, SMAD4 knockdown alleviated EMT in CSE-treated BEAS-2B cells. Mechanistically, by preventing ubiquitination-mediated SMAD4 degradation, SMAD4 directly interacted with OGT and improved SMAD4 stability. Interestingly, OGT inhibitor (OSMI-1) counteractd the effect of SMAD4-induced EMT. At the same time, overexpression of OGT promoted SMAD4 level and EMT. Hence, OGT O-GlcNAcylates and stabilizes SMAD4, which is linked to the EMT of airway epithelial cells caused by CS. Taken together, the current investigation identifies that the OGT/SMAD4 signaling pathway may be a effective COPD therapeutic target.