Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
16
10
2020
accepted:
18
02
2022
pubmed:
16
4
2022
medline:
31
5
2022
entrez:
15
4
2022
Statut:
ppublish
Résumé
Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.
Identifiants
pubmed: 35422502
doi: 10.1038/s43018-022-00348-3
pii: 10.1038/s43018-022-00348-3
pmc: PMC9551679
mid: NIHMS1825427
doi:
Substances chimiques
Histones
0
Methionine
AE28F7PNPL
Mat2a protein, mouse
EC 2.5.1.6
Methionine Adenosyltransferase
EC 2.5.1.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
629-648Subventions
Organisme : NINDS NIH HHS
ID : R01 NS115831
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS116361
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM133391
Pays : United States
Organisme : CIHR
ID : PJT-156086
Pays : Canada
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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