Detection of oncometabolite nicotine imine in the nail of oral cancer patients and predicted as an inhibitor of DNMT1

Abstract

Nicotine-metabolized product nicotine imine is suggested to play a role in metabolic changes in oral cancer. There is a significant gap in the detection of oncometabolite nicotine imine in biological fluids and nails of oral cancer patients. Oncometabolites are designated as metabolites those are usually elevated in cancer cells over normal cells. Interestingly, a direct or indirect link is missing that establishes a role of nicotine imine in pro-cancer cellular events including global DNA hypomethylation, a potential metabolic-epigenetic axis in oral cancer. A novel vertical tube gel electrophoresis (VTGE) system assisted purification and liquid chromatography-high resolution mass spectrometry (LC-HRMS) based identification of nicotine imine in the nails of oral cancer patients. Further, nicotine imine was evaluated for its molecular interactions with various methyltransferases including DNA methyltransferase 1 (DNMT1) by molecular docking and molecular dynamics (MD) simulations. Data suggested the presence of nicotine imine in the nails of oral cancer patients. Molecular docking and MD simulations revealed a specific binding affinity by nicotine imine with DNMT1. Binding by nicotine imine is within the CXCC regulatory domain of DNMT1 including key residues as ARG690, PRO574, VAL658, PRO692 and ALA695. Similar binding residues are displayed by DNMT1 inhibitor 5'-Aza-2'-deoxycytidine. Nicotine imine is suggested as a predictive biomarker for oral cancer patients in nails and this finding is a first report. Molecular docking and dynamics simulation propose the role of nicotine imine as an inhibitor of DNMT1. This work supports the involvement of synergistic pro-tumor metabolic-epigenomic axis by nicotine imine that may contribute towards potential mutagenesis of normal squamous epithelium.