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

doi:10.1016/j.celrep.2022.110453

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

Cell Rep. 2022 Mar 1;38(9):110453. doi: 10.1016/j.celrep.2022.110453.

Authors

Affiliations

¹ Department of Medicine, Division of Endocrinology, Stanford University, Stanford, CA, USA.
² Department of Chemistry, Stanford University, Stanford, CA, USA.
³ Stanford University, Stanford, CA, USA.
⁴ Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
⁵ Department of Surgery and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Pathology, Stanford School of Medicine, Stanford, CA, USA.
⁷ Department of Pediatrics and Genetics, Stanford University, Stanford, CA, USA.
⁸ Department of Medicine, Division of Endocrinology, Stanford University, Stanford, CA, USA; Endocrine Oncology Program, Stanford University, Stanford, CA, USA; Chemistry, Engineering, and Medicine for Human Health (ChEM-H) Institute, Stanford University, Stanford, CA, USA. Electronic address: jannes@stanford.edu.

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.

Keywords: SDHB; adrenal gland; ascorbate; cancer; mouse model; neuroendocrine; oncometabolite; pheochromocytoma; succinate dehydrogenase; tumor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adrenal Gland Neoplasms* / genetics
Adrenal Gland Neoplasms* / metabolism
Adrenal Gland Neoplasms* / pathology
Animals
Carcinogenesis / genetics
Cell Transformation, Neoplastic
Dioxygenases* / metabolism
Mice
Pheochromocytoma* / genetics
Pheochromocytoma* / metabolism
Pheochromocytoma* / pathology
Succinate Dehydrogenase / genetics
Succinate Dehydrogenase / metabolism
Succinates
Succinic Acid / metabolism

Substances

Succinates
Succinic Acid
Dioxygenases
Succinate Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding