Bcl2l10 induces metabolic alterations in ovarian cancer cells by regulating the TCA cycle enzymes SDHD and IDH1
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ABSTRACT:
PROVIDER: PRJNA697858 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13577075_1.fastq.gz | Fastqsanger.gz | |||
| SRR13577075_2.fastq.gz | Fastqsanger.gz | |||
| SRR13577076_1.fastq.gz | Fastqsanger.gz | |||
| SRR13577076_2.fastq.gz | Fastqsanger.gz | |||
| SRR13577077_1.fastq.gz | Fastqsanger.gz |
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Project description:The aim of this study was to identify possible downstream target genes and investigate the underlying mechanisms of action of Bcl2l10 in ovarian cancer cells. We performed RNA sequencing (RNA-Seq) and obtained a list of differentially expressed genes (DEGs) in Bcl2l10-suppressed SKOV3 and A2780 cells. RNA-Seq data showed that DEGs after Bcl2l10 knockdown are involved in transcriptional regulation and energy metabolism in ovarian cancer cells. The RNA-Seq data were validated by quantitative real-time PCR (qRT-PCR) and western blot analysis, and the levels of metabolites after Bcl2l10 knockdown were measured by ELISA. KEGG enrichment analysis showed that the commonly downregulated genes in SKOV3 and A2780 cells after Bcl2l10 knockdown were significantly enriched in metabolic pathways. The analysis of the DEGs identified from the RNA-Seq and validated by qRT-PCR revealed that succinate dehydrogenase complex subunit D (SDHD) and isocitrate dehydrogenase 1 (IDH1), which are key enzymes of the TCA cycle that regulate oncometabolite production, are potential downstream targets of Bcl2l10. We further found that Bcl2l10 knockdown induced the accumulation of succinate and isocitrate through the downregulation of SDHD and IDH1.
2021-01-30 | GSE165766 | GEO
Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.
2020-03-09 | PXD016697 | Pride
Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.
2020-03-09 | PXD016698 | Pride
Project description:New antimalarial drugs are urgently needed to control drug resistant forms of the malaria parasite, Plasmodium falciparum. Although mitochondrial metabolism is the target of both existing drugs and new lead compounds, the role of the mitochondrial tricarboxylic acid (TCA) cycle remains poorly understood. Herein, we describe 11 genetic knockout parasite lines that delete six of the eight TCA cycle enzymes. Although all TCA knockouts grew normally in asexual blood stages, these metabolic deficiencies halted lifecycle progression in later stages. Specifically, aconitase knockout parasites arrested as late gametocytes, whereas α-ketoglutarate dehydrogenase deficient parasites failed to develop oocysts in the mosquitoes. Mass-spectrometry analysis of 13C isotope-labeled TCA mutant parasites showed that P. falciparum has significant flexibility in TCA metabolism. This flexibility manifested itself through changes in pathway fluxes and through altered exchange of substrates between cytosolic and mitochondrial pools. Our findings suggest that mitochondrial metabolic plasticity is essential for parasite development . Two parallel timecourses resulting in a total of 16 samples (8 wildtype, Isocitrate Dehydrogenase/alpha-Ketogluterate Dehydrogenase double knockout) were hybridized against a Cy3-labeled reference pool of 3D7 mixed stage parasites on a two-color array.
2014-08-01 | E-GEOD-59015 | biostudies-arrayexpress
Project description:New antimalarial drugs are urgently needed to control drug resistant forms of the malaria parasite, Plasmodium falciparum. Although mitochondrial metabolism is the target of both existing drugs and new lead compounds, the role of the mitochondrial tricarboxylic acid (TCA) cycle remains poorly understood. Herein, we describe 11 genetic knockout parasite lines that delete six of the eight TCA cycle enzymes. Although all TCA knockouts grew normally in asexual blood stages, these metabolic deficiencies halted lifecycle progression in later stages. Specifically, aconitase knockout parasites arrested as late gametocytes, whereas α-ketoglutarate dehydrogenase deficient parasites failed to develop oocysts in the mosquitoes. Mass-spectrometry analysis of 13C isotope-labeled TCA mutant parasites showed that P. falciparum has significant flexibility in TCA metabolism. This flexibility manifested itself through changes in pathway fluxes and through altered exchange of substrates between cytosolic and mitochondrial pools. Our findings suggest that mitochondrial metabolic plasticity is essential for parasite development .
2014-08-01 | GSE59015 | GEO
Project description:A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been strongly implicated in synucleinopathies, including Parkinson’s disease (PD) and Lewy body dementia (LBD), but the underlying molecular basis is not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons bearing a pathological point mutation in the gene encoding α-synuclein (αSyn) protein, we report that the presence of many aberrantly S-nitrosylated proteins, including multiple tricarboxylic acid (TCA) cycle enzymes, which results in inhibition of their activity, as assessed by carbon-labeled metabolic flux experiments. The block in the TCA cycle principally affects the step at -ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing -ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death, with consequent neurodegenerative phenotypes. Our new evidence indicates that redox-mediated inhibition of the TCA cycle via aberrant protein S-nitrosylation contributes to this bioenergetic failure.
2024-10-17 | PXD036797 | Pride
Project description:Dehalogenimonas sp. TCA Genome sequencing
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Project description:The cytosolic NADP+-dependent isocitrate dehydrogenase IDH1 is frequently mutated in human cancers. Recent studies have shown that IDH1 mutant primary glioblastomas (GBM) and acute myeloid leukemias (AML) display robust association with CpG island methylator phenotype (CIMP). Such observations bring into question whether IDH1 mutations directly contribute to the development of CIMP or if the hypermethylation phenotype precedes acquisition of IDH1 mutations. To reveal the effects of IDH1 mutations on DNA methylation and gene expression, we introduced the most frequently observed IDH1 mutation, R132H, into a human cancer cell line through gene targeting. We profiled changes in methylation at over 27,000 CpG dinucleotides spanning 14,475 unique gene regions and characterized genome-wide gene expression alterations resulting from IDH1R132H knockin. We observed consistent changes in both DNA methylation and gene expression when comparing two independent IDH1R132H knockin clones to their wild-type parent, and report hypermethylation of over 2,000 loci, the majority of which contained preexisting methylation in IDH1WT parental cells. These loci exhibit the same trend in primary TCGA glioblastoma tumors with mutant IDH1 as compared to those with wild-type IDH1 and have significant overlap with genes hypermethylated in glioma-CIMP+ tumors. Furthermore, we identify specific DNA methylation and gene expression alterations which correlate with IDH1 mutations in our cell-line model as well as primary glioblastomas, including hypermethylation and transcriptional silencing of RBP1. The presented data provide insight on epigenetic alterations induced by IDH1 mutations and support a contributory role for IDH1 mutants in regulation of DNA methylation and gene expression in human cancer cells. Comparison of IDH1 R132H and wild-type HCT116 cells as well as HOG cells overexpressing either wild-type IDH1 or IDH1 R132H
2012-08-13 | E-GEOD-31133 | biostudies-arrayexpress
Project description:The cytosolic NADP+-dependent isocitrate dehydrogenase IDH1 is frequently mutated in human cancers. Recent studies have shown that IDH1 mutant primary glioblastomas (GBM) and acute myeloid leukemias (AML) display robust association with CpG island methylator phenotype (CIMP). Such observations bring into question whether IDH1 mutations directly contribute to the development of CIMP or if the hypermethylation phenotype precedes acquisition of IDH1 mutations. To reveal the effects of IDH1 mutations on DNA methylation and gene expression, we introduced the most frequently observed IDH1 mutation, R132H, into a human cancer cell line through gene targeting. We profiled changes in methylation at over 27,000 CpG dinucleotides spanning 14,475 unique gene regions and characterized genome-wide gene expression alterations resulting from IDH1R132H knockin. We observed consistent changes in both DNA methylation and gene expression when comparing two independent IDH1R132H knockin clones to their wild-type parent, and report hypermethylation of over 2,000 loci, the majority of which contained preexisting methylation in IDH1WT parental cells. These loci exhibit the same trend in primary TCGA glioblastoma tumors with mutant IDH1 as compared to those with wild-type IDH1 and have significant overlap with genes hypermethylated in glioma-CIMP+ tumors. Furthermore, we identify specific DNA methylation and gene expression alterations which correlate with IDH1 mutations in our cell-line model as well as primary glioblastomas, including hypermethylation and transcriptional silencing of RBP1. The presented data provide insight on epigenetic alterations induced by IDH1 mutations and support a contributory role for IDH1 mutants in regulation of DNA methylation and gene expression in human cancer cells. Comparison of IDH1 R132H and wild-type HCT116 cells
2012-08-13 | E-GEOD-31126 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE31126: DNA methylation alterations and transcriptional gene silencing induced by IDH1 R132H mutation [Affymetrix] GSE31133: DNA methylation alterations and transcriptional gene silencing induced by IDH1 R132H mutation [Illumina] Refer to individual Series
2012-08-12 | E-GEOD-31134 | biostudies-arrayexpress