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Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2 (MDH2)

ABSTRACT: Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2 (MDH2)

PROVIDER: PRJNA1075313 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27937330_1.fastq.gz	Fastqsanger.gz
	SRR27937330_2.fastq.gz	Fastqsanger.gz
	SRR27937331_1.fastq.gz	Fastqsanger.gz
	SRR27937331_2.fastq.gz	Fastqsanger.gz
	SRR27937332_1.fastq.gz	Fastqsanger.gz

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Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2 (MDH2)

Project description:Glioblastoma (GBM) ranks among the most lethal of human cancers with current therapies offering only palliation. GBM displays striking intratumoral heterogeneity with diversity of cell state, metabolism, and molecular regulation. Here, we demonstrate that stem-like tumor cells, designated GBM stem cells (GSCs), display higher activity of the malate aspartate shuttle (MAS) through increased expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 reduced GSC proliferation, self-renewal, and in vivo tumor growth. MDH2 targeting induced accumulation of alpha-ketoglutarate (αKG), a critical enzymatic co-factor. Mechanistically, MDH2 regulated post-transcriptional regulation of mRNA, specifically N6-Methyladenosine (m6A) with platelet-derived growth factor receptor- (PDGFR) as a regulated transcript. Leveraging these observations, targeting MDH2 and PDGFR displayed combinatorial efficacy against GSCs. Collectively, these results suggest that stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes that reveal possible therapeutic paradigms.

2024-10-15 | GSE255535 | GEO

Time-resolved analysis of proteolytic cleavage sites in Malate dehydrogenase by Trypsin.

Project description:A proteolytic cleavage experiment was performed with the protein Malate dehydrogenase (MDH) and Trypsin protease, to identify early cleavage sites in MDH. Various concentrations of Trypsin (5,000, 10,000 and 100,000 x diluted) were tested and early timepoints taken to detect only few cleavage sites in order to identify the very first events of MDH proteolysis

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Investigating the RNAs bound by Malate Dehydrgenase 2

Project description:Mitochondrial Malate Dehydrogenase 2 has been identified as an RNA-binding protein in several RNA-interactome capture studies. Here, we used eCLIP to identify the RNA targets bound by human MDH2. We identify cytosolic RNA targets for MDH2, as well as several mitochondrial tRNAs.

2024-06-26 | GSE249145 | GEO

A naturally unique variation in Al-activated malate transporter 9 determines fruit malate in cultivated tomato

Project description:Purpose: Understanding the mechanism of malate accumulation in plants is beneficial for both plant nutrient and human health. However, little is known regarding regulation of malate accumulation in horticulture plants such as tomato. The goals of this study are to investigate potential regulation network of Al-Activated Malate Transporter 9 (ALMT9) which is the major locus responsible for the variation in fruit malate concentration observed in cultivared tomato. Methods: The transcriptomes of fruit at ripening stage from CK and SlALMT9 overexpressing line1 were evaluated using single-ended sequencing of Illumina HiSeq 2500. Raw sequences were filtered and the resulting sets of clean reads were used for the following analysis by tophat and edgeR software. Results: Among 1,887 differentially expressed genes, some structural genes involved in sugar and organic acid metabolism were differently expressed in SlALMT9 overexpressing line, which partially coincide with changes of sugar and organic acid concentration. PR genes was also altered in the OX lines, in agreement with previous study that tomato fruit malate is involved in pathogen infection. Three members of malate transporters, MATE (multidrug and toxin efflux), were up-regulated (SlMATE5 and 6) or down-regulated (SlMATE9) . Besides, three sugar transport proteins and four vacuole membrane or plasma membrane proteins were up-regulated in OX line Conclusions: Using RNA-seq analysis, 1,887 differentially expressed genes was revealed. Among them, several genes related to sugar and organic acid metabolism and transport, pathogen resistances were identified. This transcriptome study provides insight into the regulatory mechanism of fruit malate accumulation and the effect of the SlALMT9 to primary metabolism.

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IMP dehydrogenase-2 drives aberrant nucleolar activity and structure in glioblastoma

Project description:Ribonucleotides serve important cellular functions as energy carriers, signaling molecules and building blocks of RNA. In eukaryotes, rRNA and tRNA synthesis in the nucleolus accounts together for over 90% of all RNA molecules. In many cancers, high proliferation rates correlated with elevation of rRNA and tRNA levels4 and nucleolar hypertrophy. However, the metabolic changes that lead to the increased nucleolar transcription and in turn foster tumorigenesis are incompletely understood. Here we show that in the highly lethal brain cancer glioblastoma (GBM), inosine monophosphate dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed. This leads to increased rRNA and tRNA synthesis and stabilization of the oncogenic GTP-binding protein nucleostemin, and enlarged and malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 reverses these malignant effects and inhibits GBM cell proliferation, whereas untransformed glia cells are unaffected. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of GBM cells even in the absence of functional p53. Our results have uncovered upregulation of IMPDH2 as a prerequisite for aberrant nucleolar function and translational capacity in GBM. This GTP metabolic reprogramming constitutes a primary event in gliomagenesis and has implications for GBM treatment and possible malignant transformation in other cancers.

2019-07-30 | GSE124727 | GEO

IMP dehydrogenase-2 drives aberrant nucleolar activity and structure in glioblastoma

Project description:IMP dehydrogenase-2 drives aberrant nucleolar activity and structure in glioblastoma

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Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

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L.hongkongensis transcriptomes grown in media supplemented with or without malate

Project description:To better understand the malate-mediated metabolism and related regulatory profiles of L. hongkongensis, we compared the respective expression profiles of L. hongkongensis cells grown in modified M63 media supplemented with or without malate using high-throughput RNA-sequencing.

2019-09-30 | GSE135058 | GEO

Microenvironmental Stiffness Induces Metabolic Reprogramming in Glioblastoma

Project description:Microenvironmental Stiffness Induces Metabolic Reprogramming in Glioblastoma

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Metabolic adaptations in LDHA/B KO GBM cells

Project description:Metabolic symbiosis in glioblastoma rely on lactate dehydrogenase expression and activity

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