DNA methylation protects cancer cells against senescence
Open accessPublished version of a preprint
Abstract
Inhibitors of DNA methylation such as 5-aza-deoxycytidine are widely used in experimental and clinical settings. However, their mechanism of action is such that DNA damage inevitably co-occurs with loss of DNA methylation, making it challenging to discern their respective effects. Here we deconvolute the effects of decreased DNA methylation and DNA damage on cancer cells, by using degron alleles of key DNA methylation regulators. We report that cancer cells with decreased DNA methylation—but no DNA damage—enter cellular senescence, with G1 arrest, SASP expression, and SA-β-gal positivity. This senescence is independent of p53 and Rb, but involves p21, which is cytoplasmic and inhibits apoptosis, and cGAS, playing a STING-independent role in the nucleus. Xenograft experiments show that tumor cells can be made senescent in vivo by decreasing DNA methylation. These findings reveal the intrinsic effects of loss of DNA methylation in cancer cells and have practical implications for future therapeutic approaches.
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Cites
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Flagged first, then by citations
- Authors
- Chen, X., Yamaguchi, K., Rodgers, B., Goehrig, D., Vindrieux, D., Lahaye, X., Nolot, M., Ferry, L., Lanciano, S., Martin, N., Dubus, P., Miura, F., Ito, T., Cristofari, G., Manel, N., Kanemaki, M. T., Bernard, D., & Defossez, P.-A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- National Institute of Genetics (JP)
- Université Paris Sciences et Lettres (FR)
- Université de Bordeaux (FR)
- Life Science Data Research Center (JP)
- Kyushu University (JP)
- Corresponding author
- Yamaguchi, Kosuke
- Defossez, Pierre-Antoine
- ORCID
- Venue
- Nature Communications
- Published
- 2025-07-01
- Volume
- 16
- Issue
- 1
- Pages
- 5901-5901
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12216915
- OpenAlex
- W4411881888
- Cited by
- 17
- References
- 14
- Citations by year
- 2026: 13 · 2025: 4
- FWCI
- 10.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche (ANR-23-CE12-0015-01)
- Institut National Du Cancer (INCA_18350)
- Fondation pour la Recherche Médicale (EQU202503019988, FDT202404018544)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- DNA methylation, cellular senescence, cancer cells, 5-aza-deoxycytidine, DNA damage, p21, cGAS, G1 cell cycle arrest, senescence-associated secretory phenotype, p53-independent senescence, tumor xenografts, apoptosis inhibition
- MeSH terms
- Senescence-Associated Secretory Phenotype, Animals, DNA Damage, Female, Humans, Mice, Nude, Neoplasms, Nucleotidyltransferases, Tumor Suppressor Protein p53, Cellular Senescence, Apoptosis, DNA Methylation, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Mice
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