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PreprintCited by 17Telomeres, Telomerase, and SenescenceEpigenetics and DNA MethylationCancer-related Molecular Pathways

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DNA methylation protects cancer cells against senescence

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Chen, Xiaoying, Yamaguchi, Kosuke, Rodgers, Brianna, Goehrig, Delphine, Vindrieux, David, Lahaye, Xavier, Nolot, Matthieu, Ferry, Laure, Martin, Nadine, Dubus, Pierre, Miura, Fumihito, Ito, Takashi, Manel, Nicolas, Kanemaki, Masato, Bernard, David, Defossez, Pierre-Antoine·2024·Nature Communications
DOI 10.1101/2024.08.23.609297PMC PMC12216915

Preprint — published as 10.1038/s41467-025-61157-7 · Paper page

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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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Metadata

Authors
Chen, X., Yamaguchi, K., Rodgers, B., Goehrig, D., Vindrieux, D., Lahaye, X., Nolot, M., Ferry, L., Martin, N., Dubus, P., Miura, F., Ito, T., Manel, N., Kanemaki, M., 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
Publisher
openRxiv
Published
2024-08-23
Volume
16
Issue
1
Pages
5901-5901
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.08.23.609297
PMC
PMC12216915
OpenAlex
W4411881888
Cited by
17
References
4
Citations by year
2026: 13 · 2025: 4
FWCI
10.94
Type
journal article
Language
en
Open access
Licence
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
  • Sidaction
  • Japan Agency for Medical Research and Development (JP23ama121022)
  • Agence Nationale de la Recherche (ANR-21-CE13-0030, 10-INBS-04, ANR-11-LABX-0071, ANR-21-CE15, 22-2-AEQ-13411, ANR‐10_INBS‐04, ANR18, ANR-23-CE12-0015, ANR-21-CE15-0037, ANR-23-CE12, ANR-23, ANR-10, ANR-18-IDEX-0001)
  • Fondation pour la Recherche Médicale (FDT202404018544, ANR-10-INBS-04, ANR-18-IDEX-0001, ANR-11-LABX-0071, EQU202503019988, EQU202103012774)
  • Fondation ARC pour la Recherche sur le Cancer (ANR-18-IDEX-0001, ANR-11-LABX-0071, ANR-10-INBS-04)
  • Centre National de la Recherche Scientifique (#ANR-18-IDEX-0001, ANR-10-INBS-04, ANR-11-LABX-0071)
  • Institut National Du Cancer (ANR-11-LABX-0071, #ANR-18-IDEX-0001, ANR-10-INBS-04, INCa-18350)
  • Fondation Bettencourt Schueller
  • Université de Paris (ANR-18- IDEX-0001, 18-IDEX-0001)
  • Japan Society for the Promotion of Science
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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