Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis.
Animals
Cell Differentiation
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Self Renewal
/ drug effects
Cell Survival
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Hematopoietic Stem Cells
/ drug effects
Histone Deacetylase Inhibitors
/ pharmacology
Histones
/ metabolism
Humans
Hydroxamic Acids
/ pharmacology
Mice
Neoplasms
/ genetics
Recurrence
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 04 2020
14 04 2020
Historique:
received:
07
03
2019
accepted:
19
03
2020
entrez:
15
4
2020
pubmed:
15
4
2020
medline:
22
7
2020
Statut:
epublish
Résumé
Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat's antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients.
Identifiants
pubmed: 32286289
doi: 10.1038/s41467-020-15615-z
pii: 10.1038/s41467-020-15615-z
pmc: PMC7156485
doi:
Substances chimiques
Histone Deacetylase Inhibitors
0
Histones
0
Hydroxamic Acids
0
quisinostat
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1792Subventions
Organisme : Cancer Research UK
ID : FC001152
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001152
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17179
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001152
Pays : United Kingdom
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