H3K27me3 conditions chemotolerance in triple-negative breast cancer - Dynamique de l'information génétique : bases fondamentales et cancer Accéder directement au contenu
Article Dans Une Revue Nature Genetics Année : 2022

H3K27me3 conditions chemotolerance in triple-negative breast cancer

Ahmed Dahmani
  • Fonction : Auteur
  • PersonId : 955396
Eric Letouzé

Résumé

The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood. Here, by monitoring epigenomes, transcriptomes and lineages with single-cell resolution, we show that the repressive histone mark H3K27me3 (trimethylation of histone H3 at lysine 27) regulates cell fate at the onset of chemotherapy. We report that a persister expression program is primed with both H3K4me3 (trimethylation of histone H3 at lysine 4) and H3K27me3 in unchallenged cells, with H3K27me3 being the lock to its transcriptional activation. We further demonstrate that depleting H3K27me3 enhances the potential of cancer cells to tolerate chemotherapy. Conversely, preventing H3K27me3 demethylation simultaneously to chemotherapy inhibits the transition to a drug-tolerant state, and delays tumor recurrence in vivo. Our results highlight how chromatin landscapes shape the potential of cancer cells to respond to initial therapy.

Mots clés

Fichier principal
Vignette du fichier
Nature_Genetics_2022_accepted.pdf (33.25 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03851953 , version 1 (21-11-2022)

Licence

Paternité

Identifiants

Citer

Justine Marsolier, Pacôme Prompsy, Adeline Durand, Anne-Marie Lyne, Camille Landragin, et al.. H3K27me3 conditions chemotolerance in triple-negative breast cancer. Nature Genetics, 2022, 54, pp.459-468. ⟨10.1038/s41588-022-01047-6⟩. ⟨hal-03851953⟩
66 Consultations
26 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More