Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N(6)-methyladenosine of Notch1

BACKGROUND: N(6)-methyladenosine (m(6)A) emerges as one of the most important modification of RNA. Bladder cancer is a common cancer type in developed countries, and hundreds of thousands of bladder cancer patients die every year. MATERIALS AND METHODS: There are various cells in bladder tumor bulk, and a small population cells defined as tumor initiating cells (TIC) have self-renewal and differentiation capacities. Bladder TICs drive bladder tumorigenesis and metastasis, and their activities are fine regulated. However, the role of N(6)-methyladenosine in bladder TIC self-renewal is unknown. RESULTS: Here, we found a decrease of N(6)-methyladenosine in bladder tumors and bladder TICs. N(6)-methyladenosine levels are related to clinical severity and outcome. Mettl14 is lowly expressed in bladder cancer and bladder TICs. Mettl14 knockout promotes the proliferation, self-renewal, metastasis and tumor initiating capacity of bladder TICs, and Mettl14 overexpression exerts an opposite role. Mettl14 and m(6)A modification participate in the RNA stability of Notch1 mRNA. Notch1 m(6)A modification inhibits its RNA stability. Notch1 plays an essential role in bladder tumorigenesis and bladder TIC self-renewal. CONCLUSION: This work reveals a novel role of Mettl14 and N(6)-methyladenosine in bladder tumorigenesis and bladder TICs, adding new layers for bladder TIC regulation and N(6)-methyladenosine function.