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

Oncotarget
John SmestadL James Maher

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 ...Continue Reading

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Citations

Nov 29, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Fatimah Al KhazalL James Maher
Apr 29, 2021·American Journal of Respiratory Cell and Molecular Biology·Joseph BalnisAriel Jaitovich

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Datasets Mentioned

BETA
SRP117182
GSE103662
SRP117088
GSE103609
GSE43298
E-GEOD-43298
PXD007874

Methods Mentioned

BETA
gene trap
PCR
RNA-seq
RRBS
confocal microscopy
acetylation

Software Mentioned

RnBeads R
imCC
ImageQuant
SAMtools
RnBeads
R
Bismark
DAVID
Bowtie
Bioconductor

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