Abstract
Cigarette smoke has been shown to trigger aberrant signaling pathways and pathophysiological processes; however, the regulatory mechanisms underlying smoke-induced gene expression remain to be established. Herein, we observed that two smoke-responsive genes, HO-1 and CYP1A1, are robustly induced upon smoke by different mechanisms in human bronchial epithelia. CYP1A1 is mediated by aryl hydrocarbon receptor signaling, while induction of HO-1 is regulated by oxidative stress, and suppressed by N-acetylcysteine treatment. In light of a pivotal role of NRF2 and BACH1 in response to oxidative stress and regulation of HO-1, we examined if smoke-induced HO-1 expression is modulated through the NRF2/BACH1 axis. We demonstrated that smoke causes significant nuclear translocation of NRF2, but only a slight decrease in nuclear BACH1. Knockdown of NRF2 attenuated smoke-induced HO-1 expression while down-regulation of BACH1 had stimulatory effects on both basal and smoke-induced HO-1 with trivial influence on NRF2 nuclear translocation. Chromatin immunoprecipitation assays showed that smoke augments promoter-specific DNA binding of NRF2 but suppresses BACH1 binding to the HO-1 promoter ARE sites, two of which at −1.0 kb and −2.6 kb are newly identified. These results suggest that the regulation of NRF2 activator and BACH1 repressor binding to the ARE sites are critical for smoke-mediated HO-1 induction.
Highlights
Cigarette smoke is one of the leading causes of lung diseases worldwide
CYP1A1 gene expression in airway epithelial cells is induced by aryl hydrocarbon receptor (AhR), which is activated by polycyclic aromatic hydrocarbons (PAHs) in smoke [3], while the mechanism of smoke-induced elevation of heme oxygenase 1 (HO-1) expression in airway epithelial cells is still incompletely elucidated
NRF2, called nuclear factor-like 2 (NFE2L2), and BACH1 are purportedly upstream of HO-1, and both belong to a class of transcription factors called the cap ‘n’ collar basic leucine zipper (CNC-BLZ) [9]
Summary
Cigarette smoke is one of the leading causes of lung diseases worldwide. Despite widespread public health policies to reduce smoking, smoking continues to be a major cause of preventable mortality and chronic diseases such as lung cancer and chronic obstructive pulmonary disease (COPD) throughout the world [1,2]. Activation of NRF2 occurs when free radicals, by virtue of modification of key cysteine residues on the KEAP1 adaptor, alters its conformation leading to NRF2 dissociation from the Cul ubiquitin ligase and translocation into the nucleus [11,12] There, it binds to DNA elements after forming heterodimers with small maf proteins [13,14]. We elucidated that in airway epithelial cells, HO-1 induction by smoke is governed by competition between NRF2 and BACH1 on the AREs in the HO-1 promoter, including two previously identified EN1 and EN2 sites and two newly identified enhancer sites, NB1 and NB2, at more proximal regions that may potentially participate in the regulation of HO-1 expression in response to cigarette smoke exposure
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