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Oncogenic SDH mutation underlies global epigenomic instability in gastrointestinal stromal tumor

ABSTRACT: We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34387 | GEO | 2013/05/22

SECONDARY ACCESSION(S): PRJNA149587

REPOSITORIES: GEO

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Oncogenic SDH mutation underlies global epigenomic instability in gastrointestinal stromal tumor

Project description:We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression. Bisulfite-converted DNA from 144 samples were analyzed with the Illumina GoldenGate Methylation Cancer Panel I array.

2013-05-22 | E-GEOD-34387 | biostudies-arrayexpress

Expression data from SDH-disabled GIST

Project description:Pediatric GIST commonly harbors a disabled succinate dehydrogenase complex (SDH), which yields tumors with highly conserved genomes but characteristic epigenomic signatures. Mysteriously, nearly half of such SDH-deficient GIST, including tumors from Carney Triad patients, lack identifiable mutations in SDH component genes and genes required for complex assembly (SDHA, SDHB, SDHC, SDHD, SDHAF, termed SDHx). Genomic sequencing coupled with DNA methylation and transcriptional profiling have exposed SDHC promoter-specific CpG island epimutation and concomitant gene silencing in the majority of SDHx-WT GIST.

2015-01-02 | GSE56670 | GEO

Expression data from SDH-disabled GIST

2015-01-02 | E-GEOD-56670 | biostudies-arrayexpress

Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs

Project description:Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood. A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH)-deficiency and global DNA hyper-methylation. Here we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary and strongly up-regulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetic state of the parental tumor, including hyper-methylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibitor, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.

2019-10-16 | GSE107447 | GEO

Gene expression analysis of SDH-deficient immortalized kidney epithelial cells

Project description:Succinate dehydrogenase (SDH) is a mitochondrial protein complex responsible for the oxidation of succinate to fumarate in the tricarboxylic acid cycle. Loss-of-function mutations in any of the SDH genes are associated with susceptibility to develop neu-roendrocrine neoplasms and renal cell carcinoma. However, the impact of SDH loss on cell metabolism and the mechanisms enabling growth of SDH-defective cells are largely unexplored. To address this issue we generated Sdhb-ablated kidney mouse cells and compared their transcriptomic profile with that of Sdhb-proficient cells. Results of this gene analysis are provided in the here deposited gene array.

2016-01-22 | E-MTAB-4349 | biostudies-arrayexpress

Succinate dehydrogenase (SDH)-Complex II regulates skeletal muscle cellular respiration and fatigue but not muscle mass in genetically induced pulmonary emphysema [20 wk]

Project description:Skeletal muscle wasting and reduced oxidative capacity coexist in patients with COPD/pulmonary emphysema and are independently associated with higher mortality. Whether reduced respiration contributes to muscle atrophy in that setting remains unknown. We have previously shown that a mouse with genetically induced COPD/pulmonary emphysema recapitulates muscle dysfunction features present in patients’ muscles, including reduced expression and activity of succinate dehydrogenase (SDH), which are partially reversed by genetic gain of SDH function. Previous research suggests that succinate accumulation, a by-product of SDH inhibition, can increase respiratory capacity of skeletal muscle. Here, we generated an inducible, muscle-specific SDH-C knockout mouse which demonstrates lower mitochondrial oxygen consumption and oxidative fibers’ contractility, associated with overall reduced exercise endurance. These changes are partially offset by mitochondrial complex I-dependent respiration, a respiratory pattern replicated in the muscles from the COPD/pulmonary emphysema genetic model. Moreover, while mice skeletal muscle SDH-C knockout causes an early succinate accumulation associated with a downregulated transcriptome, these changes do not correlate with the proteomic landscape; and animals muscle mass, fiber-type composition, and dry body mass constituents remain unaltered. We preset the first conditional, skeletal muscle-specific SDH-C knockout animal and demonstrate that while SDH-C regulates fibers respiration in genetically induced pulmonary emphysema, it does not control muscle mass.

2024-02-24 | GSE255635 | GEO

Succinate dehydrogenase (SDH)-Complex II regulates skeletal muscle cellular respiration and fatigue but not muscle mass in genetically induced pulmonary emphysema [3 wk]

2024-02-24 | GSE255632 | GEO

SDH deficiency-driven succinate accumulation dictates the drug resistance of AML through regulating p-UBC12/cullin activity

Project description:Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct microenvironment-associated metabolic processes. Here, we identified SDH deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to a wide range of anti-cancer therapies. Mechanistically, succinate promoted the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function was mediated by succinate-triggered upregulation of UBC12 phosphorylation, which impaired its E2 function in cullins neddylation. Notably, decreasing succinate levels by fludarabine could effectively restore the drug sensitivity of SDH-deficient AML PDX. Together, we uncover a novel function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.

2024-08-28 | PXD053722 | Pride

SDH deficiency-driven succinate accumulation dictates the drug resistance of AML through regulating p-UBC12/cullin activity

2024-08-28 | PXD047175 | Pride

Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-Ribose Polymerase inhibitors and low-dose alkylating chemotherapy

Project description:Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we evaluated novel treatment approaches in newly generated models of FH- and SDHB-deficient RCC.

2022-05-28 | GSE204846 | GEO

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