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Abstract
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.
Highlights
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla and autonomic sympathetic and parasympathetic paraganglia, respectively
We developed experimental (Sdhc fl/fl) and control (Sdhc fl/wt) immortalized mouse embryonic fibroblast cell lines in which Sdhc gene rearrangement can be triggered by doxycycline induction of Cre recombinase expression
Correlation of gene-specific expression change with baseline expression levels in the control cell line revealed a negative correlation (−0.178, p-value < 1E-16) between expression change and baseline expression value genomewide (Figure 2D). Further examination of this correlation using a linear fit to the full dataset revealed that genes having a baseline expression value < 6 fragments per kilobase million (FPKM) tend to increase in expression in the context of succinate dehydrogenase subunit C (SDHC)-loss, while genes having expression >6 FPKM tend to decrease in expression. This finding that patterns of SDHC-loss transcriptional change correlate with baseline expression values in normal cells has not previously been reported, and points to distinct transcriptional activating and repressing effects that operate on these gene subsets in the context of SDHC-loss
Summary
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla and autonomic sympathetic and parasympathetic paraganglia, respectively. More than 30% of PPGL are hereditary with greater than 40% penetrance depending on genotype and up to 50% develop metastases in certain hereditary germline mutations [2, 3]. Mutations in tumor-suppressing genes encoding subunits of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD, i.e. SDHx genes) and the required assembly factor that flavinates SDHA www.impactjournals.com/oncotarget (SDHAF2) can inhibit SDH activity and thereby cause hereditary and (apparently) sporadic PPGL [4,5,6,7,8,9]. Novel mutations associated with PPGL continue to be discovered. These include mutations in transmembrane protein 127 (TMEM127), myc-associated factor X (MAX) genes, somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2α (HIF2A), and pathogenic germline mutations in the FH gene encoding fumarate hydratase [10,11,12,13]
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