Research Papers:

Characterization and metabolic synthetic lethal testing in a new model of SDH-loss familial pheochromocytoma and paraganglioma

John Smestad, Oksana Hamidi, Lin Wang, Molly Nelson Holte, Fatimah Al Khazal, Luke Erber, Yue Chen and L. James Maher III _

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Oncotarget. 2018; 9:6109-6127. https://doi.org/10.18632/oncotarget.23639

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John Smestad1,2,*, Oksana Hamidi3,*, Lin Wang4, Molly Nelson Holte2, Fatimah Al Khazal2, Luke Erber5, Yue Chen5 and L. James Maher III2

1Mayo Clinic Medical Scientist Training Program, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

2Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

3Division of Endocrinology, Diabetes, and Nutrition, Mayo Clinic, Rochester, MN, USA

4Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

5Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota at Twin Cities, Minneapolis, MN, USA

*These authors contributed equally to this work and are co-first authors

Correspondence to:

L. James Maher III, email: [email protected]

Keywords: transcriptomics; epigenomics; proteomics; synthetic lethality; lactate dehydrogenase

Received: September 30, 2017     Accepted: November 20, 2017     Published: December 22, 2017


Succinate dehydrogenase (SDH)-loss pheochromocytoma and paraganglioma (PPGL) are tumors driven by metabolic derangement. SDH loss leads to accumulation of intracellular succinate, which competitively inhibits dioxygenase enzymes, causing activation of pseudohypoxic signaling and hypermethylation of histones and DNA. The mechanisms by which these alterations lead to tumorigenesis are unclear, however. In an effort to fundamentally understand how SDH loss reprograms cell biology, we developed an immortalized mouse embryonic fibroblast cell line with conditional disruption of Sdhc and characterize the kinetics of Sdhc gene rearrangement, SDHC protein loss, succinate accumulation, and the resultant hypoproliferative phenotype. We further perform global transcriptomic, epigenomic, and proteomic characterization of changes resulting from SDHC loss, identifying specific perturbations at each biological level. We compare the observed patterns of epigenomic derangement to another previously-described immortalized mouse chromaffin cell model of SDHB loss, and compare both models to human SDH-loss tumors. Finally, we perform analysis of SDHC synthetic lethality with lactate dehydrogenase A (LDHA) and pyruvate carboxylase (PCX), which are important for regeneration of NAD+ and aspartate biosynthesis, respectively. Our data show that SDH-loss cells are selectively vulnerable to LDH genetic knock-down or chemical inhibition, suggesting that LDH inhibition may be an effective therapeutic strategy for SDH-loss PPGL.

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