Epigenetic regulation of CXC chemokine expression by environmental electrophiles through inhibition of DNA methyltransferase activity

Environmental electrophiles, which are ubiquitously distributed covalently modify DNA and proteins, potentially leading to adverse health effects. However, the impact of individual electrophiles on target proteins and their physiological roles remains largely unknown. In this study, we focused on DNA methylation, which regulates gene expression and physiological responses. We screened 45 environmental electrophiles for their inhibitory effects of DNA methyltransferase 3B (DNMT3B) activity, a key enzyme for DNA methylation. We found that four electrophiles significantly attenuated DNMT3B enzyme activity. Interestingly, we found that 1,2-naphthoquinone (1,2-NQ), an air pollutant, binds to lysine 662, which is located near the active site in DNMT3B. 1,2-NQ widely altered gene expression and evoked inflammatory responses in lung adenocarcinoma cell lines. Furthermore, we found that epigenetic dysregulation of CXCL8 by 1,2-NQ upregulates CXCL8 expression and promotes cancer cell growth. Our study provides novel mechanisms of epigenetic regulation by environmental electrophiles through the inhibition of DNMT3B activity and suggests their physiological impact.