The emerging role of N-methyladenine RNA methylation in metal ion metabolism and metal-induced carcinogenesis.

N-methyladenine (mA) is the most common and abundant internal modification in eukaryotic mRNAs, which can regulate gene expression and perform important biological tasks. Metal ions participate in nucleotide biosynthesis and repair, signal transduction, energy generation, immune defense, and other important metabolic processes. However, long-term environmental and occupational exposure to metals through food, air, soil, water, and industry can result in toxicity, serious health problems, and cancer. Recent evidence indicates dynamic and reversible mA modification modulates various metal ion metabolism, such as iron absorption, calcium uptake and transport. In turn, environmental heavy metal can alter mA modification by directly affecting catalytic activity and expression level of methyltransferases and demethylases, or through reactive oxygen species, eventually disrupting normal biological function and leading to diseases. Therefore, mA RNA methylation may play a bridging role in heavy metal pollution-induced carcinogenesis. This review discusses interaction among heavy metal, mA, and metal ions metabolism, and their regulatory mechanism, focuses on the role of mA methylation and heavy metal pollution in cancer. Finally, the role of nutritional therapy that targeting mA methylation to prevent metal ion metabolism disorder-induced cancer is summarized.