m⁶ A-Dependent Modulation via IGF2BP3/MCM5/Notch Axis Promotes Partial EMT and LUAD Metastasis

The importance of mRNA N6-methyladenosine (m⁶ A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity is shaped by m⁶ A modification is interesting but remains uncharacterized. Here, this work shows that m⁶ A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is remarkably upregulated in metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis of patients. Interestingly, IGF2BP3 induces partial epithelial-mesenchymal-transition (EMT) and confers LUAD cells plasticity to metastasize through m⁶ A-dependent overactivation of Notch signaling. Mechanistically, IGF2BP3 recognized m⁶ A-modified minichromosome maintenance complex component (MCM5) mRNAs to prolong stability of them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizes NICD1 protein and contributes to m⁶ A-dependent IGF2BP3-mediated cellular plasticity. Notably, a tight correlation of the IGF2BP3/MCM5/Notch axis is evidenced in clinical LUAD specimens. Therefore, this study elucidates a critical role of m⁶ A modification on LUAD cell plasticity in fostering tumor metastasis via the above axis, providing potential targets for metastatic LUAD.