Cigarette smoking induces aberrant N6-methyladenosine of DAPK2 to promote non-small cell lung cancer progression by activating NF-ΚB pathway

N6-methyladenosine (m6A) has recently emerged as an important regulatory mechanism for gene expression and aberrant m6A modification plays an important role in tumor progression. Emerging evidence has shown that aberrant m6A modification induced by cigarette smoking is involved in carcinogenesis, but whether cigarette smoking affects m6A modification and thus deteriorates to non-small cell lung cancer (NSCLC) is still unclear. Here, we identified a tumor suppressor gene-DAPK2 which was significantly associated with poor prognosis of NSCLC patients, especially in patients with a smoking history. Low levels of DAPK2 were detected in smokers and in NSCLC tissues. Cigarette smoking induced aberrant N6-methyladenosine modification of DAPK2, which resulted in decreased DAPK2 mRNA stability and expression of its mRNA and protein. This modification was mediated by the m6A writer METTL3 and the m6A reader YTHDF2. Mechanistically, we further demonstrated that DAPK2 functions as a tumor suppressor and downregulation of DAPK2 substantially enhances the proliferation and migration abilities in vitro and in vivo by activating NF-kappa B signaling pathway. Notably, the BAY 11-7085, a NF-kappa B signaling selective inhibitor, was shown to efficiently suppressed downregulation of DAPK2induced oncogenic phenotypes of NSCLC cells. Our study reveals that cigarette smoking induces aberrant N6methyladenosine of DAPK2 to promote NSCLC progression, which provides new insight into the mechanisms of NSCLC progression and a specific therapeutic target for NSCLC patients with a smoking history.

Automated summary

This study reveals that cigarette smoking induces aberrant N6-methyladenosine modification of DAPK2, promoting the progression of NSCLC. DAPK2 acts as a tumor suppressor, and downregulation enhances proliferation and migration abilities of NSCLC cells. Selective inhibition of NF-kappa B signaling pathway effectively suppresses DAPK2-induced oncogenic phenotypes in NSCLC cells.