METTL3 promotes cellular senescence of colorectal cancer via modulation of CDKN2B transcription and mRNA stability.
Zhuo-Jia ChenJiawang ZhouYou WuFeng ChenJianing LiLijun TaoYifan TianHaoran WangJiexin LiZigang LiWeiling HeKun ZhangHong-Sheng WangPublished in: Oncogene (2024)
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 (m 6 A) and methyltransferase METTL3. Knockdown of METTL3 can restore the senescence-associated secretory phenotype (SASP) of CRC cells. Our findings, which were confirmed by m 6 A-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, m 6 A 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.
Keyphrases
- dna damage
- endothelial cells
- stress induced
- binding protein
- induced apoptosis
- dna methylation
- transcription factor
- high glucose
- single cell
- cell cycle arrest
- oxidative stress
- quantum dots
- mesenchymal stem cells
- dendritic cells
- genome wide
- young adults
- endoplasmic reticulum stress
- immune response
- cancer therapy
- risk assessment
- squamous cell
- human health