Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells.
fatty acid oxidation
metabolism
neural stem cells
p53
quiescence
tumour initiation
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
22 05 2023
22 05 2023
Historique:
received:
17
01
2021
revised:
09
12
2021
accepted:
28
03
2023
medline:
25
5
2023
pubmed:
22
4
2023
entrez:
21
04
2023
Statut:
ppublish
Résumé
Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear. Here, we show that p53 maintains quiescence by inducing fatty-acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention.
Identifiants
pubmed: 37084728
pii: S1534-5807(23)00148-X
doi: 10.1016/j.devcel.2023.03.021
pmc: PMC10618406
pii:
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
PPAR alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
836-846.e6Subventions
Organisme : Wellcome Trust
ID : 104566/Z/14/Z
Pays : United Kingdom
Organisme : Department of Health
ID : NIHR-INF-0389
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : FC001088
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 27590
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC-A658-5TY20
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C55501/A21203
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_A652_1002
Pays : United Kingdom
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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