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Mitochondrial DNA Alterations Underlie an Irreversible Shift to Aerobic Glycolysis in Fumarate Hydratase-deficient Renal Cancer

ABSTRACT: Mitochondrial DNA Alterations Underlie an Irreversible Shift to Aerobic Glycolysis in Fumarate Hydratase-deficient Renal Cancer

PROVIDER: PRJNA660663 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12563600_1.fastq.gz	Fastqsanger.gz
	SRR12563600_2.fastq.gz	Fastqsanger.gz
	SRR12563601_1.fastq.gz	Fastqsanger.gz
	SRR12563601_2.fastq.gz	Fastqsanger.gz
	SRR12563602_1.fastq.gz	Fastqsanger.gz

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Mitochondrial DNA Alterations Underlie an Irreversible Shift to Aerobic Glycolysis in Fumarate Hydratase-deficient Renal Cancer

Project description:Understanding the mechanisms of the Warburg shift to aerobic glycolysis is central to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by bi-allelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed of the mitochondrial in tumors from HLRCC patients. Biochemical and transcriptomics analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of expression of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.

2021-01-22 | GSE157256 | GEO

Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer.

Project description:Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.

| S-EPMC8039187 | biostudies-literature

Transcription profiling of human fibriods vs. normal myometrium with mutated or wild type fumarate hydratase (FH) gene reveals distinct expression profiles in fumarate-hydratase-deficient uterine fibroids.

Project description:A series of gene expression measurements of normal myometrium and uterine fibroids with mutated or wild-type fumarate hydratase (FH) gene.

2007-10-02 | E-GEOD-2725 | biostudies-arrayexpress

Transcription profiling of human uterine fibroids with mutated or wild type fumarate hydratase gene

Project description:A series of gene expression measurements of uterine fibroids with mutated or wild-type fumarate hydratase (FH) gene.

2007-08-25 | E-GEOD-2152 | biostudies-arrayexpress

Fumarate induces vesicular release of mtDNA to drive innate immunity

Project description:Fumarate Hydratase (FH) is an enzyme of the Tricarboxilic Acid Cycle (TCA) that catalyzes the conversion of fumarate into malate. In the last decade, studies have revealed FH as a bona fide tumour suppressor whose mutations cause Hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate. Yet, whilst the long-term consequences of FH loss have been extensively described, the acute response to FH loss has not been investigated due, in part, to the lack of a suitable model. Here, we generated a new inducible mouse model to investigate the chronology of the murine homologue of FH, Fh1, loss in the adult kidney.

2023-02-17 | GSE183745 | GEO

A chemoproteomic portrait of the oncometabolite fumarate

Project description:Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth and survival. Understanding these mechanisms and developing biomarkers to identify their presence thus represents a vital goal. Towards this goal, here we report a chemoproteomic map of the covalent targets of fumarate, an oncometabolite whose accumulation marks the genetic cancer predisposition syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). First, we validate the ability of known and novel chemoproteomic probes to report on concentration-dependent fumarate reactivity in vitro. Next, we apply these probes in concert with LC-MS/MS to identify cysteine residues sensitive to either fumarate treatment or fumarate hydratase (FH) mutation in untransformed and HLRCC cell models, respectively. Mining this data to understand the structural determinants of fumarate reactivity led to the discovery of an unexpected anti-correlation with nucleophilicity, indicating a novel influence of pH on fumarate-cysteine interactions. Finally, we show that many fumarate-sensitive and FH-regulated cysteines are found in functional protein domains, and perform functional studies of a fumarate-sensitive cysteine in SMARCC1 that lies at a key protein-protein interface in the SWI-SNF tumor suppressor complex. Our studies provide a powerful resource for understanding the influence of fumarate on reactive cysteine residues, and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.

2018-11-27 | PXD009378 | Pride

Expression data from mouse kidney epithelial cells

Project description:Fumarate hydratase (FH) is the enzyme in the Krebs cycle, which transforms fumarate to malate. Loss of fumarate hyrdragase leads to hereditary leiomyomatosis and renal cell cancer (HLRCC). The biallelic inactivation has been highly accumulated in FH-deficient cells and is considered a major pro-oncogenic factor for HLRCC tumorigenesis. We used microarrays to understand the global readaptation of cell metabolism of gene expression underlying the truncated Krebs cycle by loss of function of fumarate hydratase. The fumarate hydratase wild type and knock out cells were generated for RNA extraction and hybridization on Affymetrix microarrays.

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Fumarate effect on the Escherichia coli proteome at aerobic and anaerobic growth conditions

Project description:The changes in protein composition of E. coli were studied in a global proteomic approach for aerobic growth without or with fumarate as carbon source (glycerol + O2, fumarate + O2, respectively) and anaerobic growth without or with fumarate as carbon source (glycerol + DMSO, glycerol + DMSO + fumarate, respectively). The experiments should unravel the changes in response to fumarate under aerobic (i) and anaerobic (ii) conditions, and more generally (iii) the fumarate proteome under aerobic versus anaerobic conditions. Fumarate was used as the C4DC due to its capability to support aerobic and anaerobic growth, and glycerol was used as the alternative carbon source that exerts no or only weak carbon catabolite repression.

2019-11-20 | PXD011760 | Pride

Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma [Ribosome_Profiling]

Project description:Metabolic reprogramming is a hallmark of cancer that facilitates changes in many adaptive biological processes. Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) lead to fumarate accumulation and cause hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is a rare, inherited disease characterized by the development of non-cancerous smooth muscle tumors of the uterus and skin, and an increased risk of a highly metastatic and aggressive form of kidney cancer. Fumarate has been shown to inhibit 2-oxyglutarate-dependent dioxygenases (2OGDDs) involved in the hydroxylation of HIF1α, as well as in DNA and histone demethylation. However, the link between fumarate accumulation and changes in RNA post-transcriptional modifications has not been defined. Here, we determine the consequences of fumarate accumulation on the activity of different members of the 2OGDD family targeting RNA modifications. By evaluating multiple RNA modifications in patient-derived HLRCC cell lines, we show that mutation of FH selectively alters the activity of demethylases acting upon N6-methyladenosine (m6A), while the demethylases acting upon N1-methyladenosine (m1A) and 5-formylcytosine (f5C) in mitochondrial RNA are unaffected. The observation that metabolites may modulate specific subsets of RNA-modifying enzymes offers new insights into their gene regulatory effects and potential strategies for therapeutic intervention.

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Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma [m1A_pileup]

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