SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas

Neali Armstrong, Claire M. Storey, Sarah E. Noll, Katherine Margulis, Myat Han Soe, Haixia Xu, Benjamin Yeh, Lauren Fishbein, Electron Kebebew, Brooke E. Howitt, Richard N. Zare, Julien Sage, Justin P. Annes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageAmerican English
Article number110453
JournalCell Reports
Volume38
Issue number9
DOIs
StatePublished - 1 Mar 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Authors

Keywords

  • SDHB
  • adrenal gland
  • ascorbate
  • cancer
  • mouse model
  • neuroendocrine
  • oncometabolite
  • pheochromocytoma
  • succinate dehydrogenase
  • tumor

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