Abstract
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 p15INK4B) 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.
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Data availability
m6A-seq data are available through SRA, PRJNA841050. The detailed procedures of methods, eight figures and four tables are attached. All study data are included in the article and/or Supplementary materials.
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Acknowledgements
We thank Prof Hao Liu at the Cancer Center of Guangzhou Medical University for plasmid donation, experimental skills and instrumental help.
Funding
This research was supported by the National Key Research and Development Program of China (No. 2022YFC2601800, and 2022YFC3401000), the National Natural Science Foundation of China (Nos. 32161143017, 82173833, 82372743, 82173126, 81973343, 82272658, 82373893, and 82022037), the Guangdong Basic and Applied Basic Research Foundation (Nos. 2023B1515040006, and 2021B1515230009), the Open Program of Shenzhen Bay Laboratory (No. SZBL202009051006), the Guangdong Provincial Key Laboratory of Construction Foundation (2023B1212060022), the Guangdong Provincial Natural Science Foundation (2019B151502063), the Sichuan Science and Technology Program (Nos. 2022JDRC0042, and 2022NSFSC0776), the Joint Research Foundation of Chengdu Medical College and the Seventh People’s Hospital (Grant Nos. 2022LHTD-02, 2021LHJYPJ-08 and 2022488), and the Shenzhen Bay Scholars Program.
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HS Wang, ZJ Chen, ZG Li, Q Peng, W He, and JX Li designed and initiated the study; Y Wu, F Chen, JW Zhou, K Zhong, and HR Wang performed experiments; HS Zhang, JN Li, LJ Tao, and YF Tian helped design the study and interpret the data; ZJ Chen and HS Wang wrote the paper.
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Chen, Z., Zhou, J., Wu, Y. et al. METTL3 promotes cellular senescence of colorectal cancer via modulation of CDKN2B transcription and mRNA stability. Oncogene 43, 976–991 (2024). https://doi.org/10.1038/s41388-024-02956-y
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DOI: https://doi.org/10.1038/s41388-024-02956-y
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