SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas.
SDHB
adrenal gland
ascorbate
cancer
mouse model
neuroendocrine
oncometabolite
pheochromocytoma
succinate dehydrogenase
tumor
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
01 03 2022
01 03 2022
Historique:
received:
08
07
2021
revised:
03
11
2021
accepted:
07
02
2022
entrez:
2
3
2022
pubmed:
3
3
2022
medline:
12
4
2022
Statut:
ppublish
Résumé
Inherited pathogenic succinate dehydrogenase (SDHx) gene mutations cause the hereditary pheochromocytoma and paraganglioma tumor syndrome. Syndromic tumors exhibit elevated succinate, an oncometabolite that is proposed to drive tumorigenesis via DNA and histone hypermethylation, mitochondrial expansion, and pseudohypoxia-related gene expression. To interrogate this prevailing model, we disrupt mouse adrenal medulla SDHB expression, which recapitulates several key molecular features of human SDHx tumors, including succinate accumulation but not 5hmC loss, HIF accumulation, or tumorigenesis. By contrast, concomitant SDHB and the neurofibromin 1 tumor suppressor disruption yields SDHx-like pheochromocytomas. Unexpectedly, in vivo depletion of the 2-oxoglutarate (2-OG) dioxygenase cofactor ascorbate reduces SDHB-deficient cell survival, indicating that SDHx loss may be better tolerated by tissues with high antioxidant capacity. Contrary to the prevailing oncometabolite model, succinate accumulation and 2-OG-dependent dioxygenase inhibition are insufficient for mouse pheochromocytoma tumorigenesis, which requires additional growth-regulatory pathway activation.
Identifiants
pubmed: 35235785
pii: S2211-1247(22)00180-2
doi: 10.1016/j.celrep.2022.110453
pmc: PMC8939053
mid: NIHMS1785223
pii:
doi:
Substances chimiques
Succinates
0
Succinic Acid
AB6MNQ6J6L
Dioxygenases
EC 1.13.11.-
Succinate Dehydrogenase
EC 1.3.99.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
110453Subventions
Organisme : NCI NIH HHS
ID : T32 CA009302
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119955
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA246586
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101530
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA231997
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR003142
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. 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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