METTL3 promotes cellular senescence of colorectal cancer via modulation of CDKN2B transcription and mRNA stability

Cellular senescence plays a critical role in cancer development, but the underlying mechanisms remain poorly understood. Our recent study uncovered that replicative senescent colorectal cancer (CRC) cells exhibit increased levels of mRNA N6-methyladenosine (m⁶A) and methyltransferase METTL3. Knockdown of METTL3 can restore the senescence-associated secretory phenotype (SASP) of CRC cells. Our findings, which were confirmed by m⁶A-sequencing and functional studies, demonstrate that the cyclin-dependent kinase inhibitor 2B (CDKN2B, encoding p15^INK4B) is a mediator of METTL3-regulated CRC senescence. Specifically, m⁶A modification at position A413 in the coding sequence (CDS) of CDKN2B positively regulates its mRNA stability by recruiting IGF2BP3 and preventing binding with the CCR4-NOT complex. Moreover, increased METTL3 methylates and stabilizes the mRNA of E2F1, which binds to the −208 to −198 regions of the CDKN2B promoter to facilitate transcription. Inhibition of METTL3 or specifically targeting CDKN2B methylation can suppress CRC senescence. Finally, the METTL3/CDKN2B axis-induced senescence can facilitate M2 macrophage polarization and is correlated with aging and CRC progression. The involvement of METTL3/CDKN2B in cell senescence provides a new potential therapeutic target for CRC treatment and expands our understanding of mRNA methylation’s role in cellular senescence.