RNA m6A methyltransferase METTL3 regulates invasiveness of melanoma cells by matrix metallopeptidase 2

The development of immunotherapy has improved the treatment of melanoma; however, resistance and frequent recurrence persist and remain a major problem. N 6 -methyladenosine (m 6 A) is the most abundant epitranscriptomic mark on mRNA and is essential for various physiological processes; however, its role in melanoma is unknown. Utilizing human normal melanocyte and melanoma cell lines, we analyzed the expression of METTL3 by quantitative RT-PCR. We inhibited the METTL3 expression by shRNA and analyzed the effects on melanoma cell proliferation, colony formation ability, and invasion. Finally, we assessed the role of METTL3 by using wild-type and m 6 A catalytic site mutant METTL3. Melanoma cell lines express higher levels of METTL3, as compared with normal melanocytes. Interestingly, silencing of METTL3 gene expression in melanoma cells resulted in decreased m 6 A activity, colony formation and invasiveness, while its overexpression led to increased m 6 A activity, colony formation and invasion. METTL3 overexpression promotes accumulation of MMP2 and N-cadherin in melanoma cells. Strikingly, the overexpression of m 6 A catalytic site mutant METTL3 was unable to produce a similar increase in MMP2 expression, suggesting that m 6 A activity of METTL3 is important for melanoma cell invasiveness. Our results for the first time uncover the role of m 6 A modification in melanoma cell biology. We show that METTL3 is upregulated in human melanoma and plays a role in invasion/migration through MMP2. These findings provide the framework for the development and use of METTL3 inhibitors in melanoma treatment.