H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
21
09
2021
accepted:
16
03
2022
revised:
11
03
2022
pubmed:
31
3
2022
medline:
4
5
2022
entrez:
30
3
2022
Statut:
ppublish
Résumé
The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated with increased tumor cell apoptosis. Inhibition of aerobic glycolysis enzyme LDHA and G6PD had no significant effects on tumor cell survival. Ablation of G6PD had no significant effect on human mesothelioma and colon carcinoma xenograft growth in athymic mice. However, activation of G6PD with the G6PD-selective activator AG1 induced tumor cell death. AG1 increased tumor cell ROS production and the resultant extrinsic and intrinsic death pathways, mitochondrial processes, and unfolded protein response in tumor cells. Consistent with increased tumor cell death in vitro, AG1 suppressed human mesothelioma xenograft growth in a dose-dependent manner in vivo. Furthermore, AG1 treatment significantly increased tumor-bearing mouse survival in an intra-peritoneum xenograft athymic mouse model. Therefore, in human mesothelioma and colon carcinoma, G6PD is not essential for tumor growth. G6PD acts as a metabolic checkpoint to control metabolic flux towards the PPP to promote tumor cell apoptosis, and its expression is repressed by its promotor H3K9me3 deposition.
Identifiants
pubmed: 35351997
doi: 10.1038/s41388-022-02283-0
pii: 10.1038/s41388-022-02283-0
pmc: PMC9058223
mid: NIHMS1790143
doi:
Substances chimiques
Reactive Oxygen Species
0
Glucosephosphate Dehydrogenase
EC 1.1.1.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2651-2662Subventions
Organisme : NCI NIH HHS
ID : R01 CA236890
Pays : United States
Organisme : CSRD VA
ID : I01 CX001364
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA125066
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190429
Pays : United States
Organisme : BLRD VA
ID : IS1 BX004009
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227433
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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