| Abstract |
N6-methyladenosine (m6A) is the most abundant internal modification in mammalian
mRNAs. Despite its functional importance in various physiological events, the
role of m6A in chemical carcinogenesis remains largely unknown. Here we profiled
the dynamic m6A mRNA modification during cellular transformation induced by
chemical carcinogens and identified a subset of cell transformation-related,
concordantly modulated m6A sites. Notably, the increased m6A in 3'-UTR mRNA of
oncogene CDCP1 was found in malignant transformed cells. Mechanistically, the
m6A methyltransferase METTL3 and demethylases ALKBH5 mediate the m6A
modification in 3'-UTR of CDCP1 mRNA. METTL3 and m6A reader YTHDF1
preferentially recognize m6A 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-m6A-CDCP1 axis resulted in decreased growth and progression of
chemical-transformed cells and bladder cancer cells. Most importantly,
METTL3-m6A-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
m6A modification in chemical-induced malignant transformation and provide
insight into critical roles of the METTL3-m6A-CDCP1 axis in chemical
carcinogenesis. |
