DNA methylation protects cancer cells against senescence

Xiaoying Chen, Kosuke Yamaguchi (), Brianna Rodgers, Delphine Goehrig, David Vindrieux, Xavier Lahaye, Matthieu Nolot, Laure Ferry, Sophie Lanciano, Nadine Martin, Pierre Dubus, Fumihito Miura, Takashi Ito, Gael Cristofari, Nicolas Manel, Masato T. Kanemaki, David Bernard and Pierre-Antoine Defossez ()
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Xiaoying Chen: Epigenetics and Cell Fate
Kosuke Yamaguchi: Epigenetics and Cell Fate
Brianna Rodgers: Epigenetics and Cell Fate
Delphine Goehrig: Université de Lyon
David Vindrieux: Université de Lyon
Xavier Lahaye: PSL Research University
Matthieu Nolot: Epigenetics and Cell Fate
Laure Ferry: Epigenetics and Cell Fate
Sophie Lanciano: Institute for Research on Cancer and Aging of Nice (IRCAN)
Nadine Martin: Université de Lyon
Pierre Dubus: Centre Hospitalier Universitaire de Bordeaux
Fumihito Miura: the University of Tokyo
Takashi Ito: Kyushu University Graduate School of Medical Sciences
Gael Cristofari: Institute for Research on Cancer and Aging of Nice (IRCAN)
Nicolas Manel: PSL Research University
Masato T. Kanemaki: Research Organization of Information and Systems (ROIS)
David Bernard: Université de Lyon
Pierre-Antoine Defossez: Epigenetics and Cell Fate

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61157-7

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