Dynamic m6A mRNA methylation reveals the role of METTL3-m6A-CDCP1 signaling axis in chemical carcinogenesis

N6-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNAs. Despite its functional importance in various physiological events, the role of m(6)A in chemical carcinogenesis remains largely unknown. Here we profiled the dynamic m(6)A mRNA modification during cellular transformation induced by chemical carcinogens and identified a subset of cell transformation-related, concordantly modulated m(6)A sites. Notably, the increased m(6)A in 3'-UTR mRNA of oncogene CDCP1 was found in malignant transformed cells. Mechanistically, the m(6)A methyltransferase METTL3 and demethylases ALKBH5 mediate the m(6)A modification in 3'-UTR of CDCP1 mRNA. METTL3 and m(6)A reader YTHDF1 preferentially recognize m(6)A residues on CPCP1 3'-UTR and promote CDCP1 translation. We further showed that METTL3 and CDCP1 are upregulated in the bladder cancer patient samples and the expression of METTL3 and CDCP1 is correlated with the progression status of the bladder cancers. Inhibition of the METTL3-m(6)A-CDCP1 axis resulted in decreased growth and progression of chemical-transformed cells and bladder cancer cells. Most importantly, METTL3-m(6)A-CDCP1 axis has synergistic effect with chemical carcinogens in promoting malignant transformation of uroepithelial cells and bladder cancer tumorigenesis in vitro and in vivo. Taken together, our results identify dynamic m(6)A modification in chemical-induced malignant transformation and provide insight into critical roles of the METTL3-m(6)A-CDCP1 axis in chemical carcinogenesis.