H3K27me3 conditions chemotolerance in triple-negative breast cancer.

Drug Resistance, Neoplasm / genetics Histones / genetics Humans Lysine / metabolism Methylation Neoplasm Recurrence, Local Triple Negative Breast Neoplasms / drug therapy

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
04 2022
Historique:
received: 21 12 2021
accepted: 04 03 2022
pubmed: 13 4 2022
medline: 15 4 2022
entrez: 12 4 2022
Statut: ppublish

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.

Identifiants

DOI: 10.1038/s41588-022-01047-6 PMID: 35410383 PMC: PMC7612638
pubmed: 35410383
doi: 10.1038/s41588-022-01047-6
pii: 10.1038/s41588-022-01047-6
pmc: PMC7612638
mid: EMS143938
doi:

Substances chimiques

Histones 0
histone H3 trimethyl Lys4 0
Lysine K3Z4F929H6

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

459-468

Subventions

Organisme : European Research Council
ID : 758170
Pays : International
Organisme : European Research Council
ID : 948528
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA148761
Pays : United States

Informations de copyright

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Auteurs

Justine Marsolier (J)

CNRS UMR3244, Institut Curie, PSL University, Paris, France.
Translational Research Department, Institut Curie, PSL University, Paris, France.
ORCID: 0000-0001-8464-9306

Pacôme Prompsy (P)

CNRS UMR3244, Institut Curie, PSL University, Paris, France.
Translational Research Department, Institut Curie, PSL University, Paris, France.

Adeline Durand (A)

CNRS UMR3244, Institut Curie, PSL University, Paris, France.
Translational Research Department, Institut Curie, PSL University, Paris, France.
ORCID: 0000-0002-7423-2504

Anne-Marie Lyne (AM)

CNRS UMR168, Institut Curie, PSL University, Sorbonne University, Paris, France.

Camille Landragin (C)

CNRS UMR3244, Institut Curie, PSL University, Paris, France.
Translational Research Department, Institut Curie, PSL University, Paris, France.

Amandine Trouchet (A)

CNRS UMR3244, Institut Curie, PSL University, Paris, France.
Single Cell Initiative, Institut Curie, PSL University, Paris, France.

Sabrina Tenreira Bento (ST)

CNRS UMR168, Institut Curie, PSL University, Sorbonne University, Paris, France.

Almut Eisele (A)

CNRS UMR168, Institut Curie, PSL University, Sorbonne University, Paris, France.

Sophie Foulon (S)

CNRS UMR8231, ESPCI Paris, PSL University, Paris, France.

Léa Baudre (L)

CNRS UMR3244, Institut Curie, PSL University, Paris, France.
Translational Research Department, Institut Curie, PSL University, Paris, France.

Kevin Grosselin (K)

CNRS UMR8231, ESPCI Paris, PSL University, Paris, France.
HiFiBio SAS, Paris, France.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Mylène Bohec (M)

Single Cell Initiative, Institut Curie, PSL University, Paris, France.
Genomics of Excellence (ICGex) Platform, Institut Curie, PSL University, Paris, France.

Sylvain Baulande (S)

Single Cell Initiative, Institut Curie, PSL University, Paris, France.
Genomics of Excellence (ICGex) Platform, Institut Curie, PSL University, Paris, France.
ORCID: 0000-0003-3104-1684

Ahmed Dahmani (A)

Translational Research Department, Institut Curie, PSL University, Paris, France.

Laura Sourd (L)

Translational Research Department, Institut Curie, PSL University, Paris, France.

Eric Letouzé (E)

Functional Genomics of Solid Tumors laboratory, Centre de Recherche des Cordeliers, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris, France.
ORCID: 0000-0002-6369-2839

Anne-Vincent Salomon (AV)

Department of Pathology-Genetics and Immunology, Institut Curie, PSL Research University, Paris, France.
INSERM U934, Institut Curie, PSL Research University, Paris, France.
ORCID: 0000-0001-5754-5771

Elisabetta Marangoni (E)

Translational Research Department, Institut Curie, PSL University, Paris, France.
ORCID: 0000-0002-3337-6448

Leïla Perié (L)

CNRS UMR168, Institut Curie, PSL University, Sorbonne University, Paris, France.
ORCID: 0000-0003-0798-4498

Céline Vallot (C)

CNRS UMR3244, Institut Curie, PSL University, Paris, France. celine.vallot@curie.fr.
Translational Research Department, Institut Curie, PSL University, Paris, France. celine.vallot@curie.fr.
ORCID: 0000-0003-1601-2359

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › H3K27me3 conditions chemotolerance in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › H3K27me3 conditions chemotolerance in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › H3K27me3 conditions chemotolerance in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés essentiels › Lysine › H3K27me3 conditions chemotolerance in...
questionsmedicales.fr › Métabolisme › Alkylation › Méthylation › H3K27me3 conditions chemotolerance in...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › H3K27me3 conditions chemotolerance in...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Tumeurs du sein triple-négatives › H3K27me3 conditions chemotolerance in...