Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA137189 | ENA |
REPOSITORIES: ENA
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Project description:Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates and redox potential required for the generation of biomass. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. SIRT3 loss promotes a metabolic profile consistent with high glycolysis required for anabolic processes in vivo and in vitro. Mechanistically, SIRT3 mediates metabolic reprogramming independently of mitochondrial oxidative metabolism and through HIF1a, a transcription factor that controls expression of key glycolytic enzymes. SIRT3 loss increases reactive oxygen species production, resulting in enhanced HIF1a stabilization. Strikingly, SIRT3 is deleted in 40% of human breast cancers, and its loss correlates with the upregulation of HIF1a target genes. Finally, we find that SIRT3 overexpression directly represses the Warburg effect in breast cancer cells. In sum, we identify SIRT3 as a regulator of HIF1a and a suppressor of the Warburg effect. RNA isolated from brown adipose tissue of SIRT3 WT and KO mice. 5 wild-type samples and 5 SIRT3 KO samples
2011-03-15 | E-GEOD-27309 | biostudies-arrayexpress
Project description:Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates and redox potential required for the generation of biomass. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. SIRT3 loss promotes a metabolic profile consistent with high glycolysis required for anabolic processes in vivo and in vitro. Mechanistically, SIRT3 mediates metabolic reprogramming independently of mitochondrial oxidative metabolism and through HIF1a, a transcription factor that controls expression of key glycolytic enzymes. SIRT3 loss increases reactive oxygen species production, resulting in enhanced HIF1a stabilization. Strikingly, SIRT3 is deleted in 40% of human breast cancers, and its loss correlates with the upregulation of HIF1a target genes. Finally, we find that SIRT3 overexpression directly represses the Warburg effect in breast cancer cells. In sum, we identify SIRT3 as a regulator of HIF1a and a suppressor of the Warburg effect.
2011-03-15 | GSE27309 | GEO
Project description:In this study, we investigated sex-specific differences in gene expression caused by Sirt3 knockout. SIRT3, a mitochondrial deacetylase, plays a crucial role in maintaining cellular health. Through activation or suppression of a large number of target proteins, it integrates various metabolic processes, including energy production and antioxidant defense. Using NGS mRNA-seq on wild-type and Sirt3-knock-out male and female mouse embryonic fibroblasts (MEFs) we detected significant changes in both global gene signature and affected cellular pathways. More importantly, we describe major differences in metabolic status of male and female KO MEFs which include fundamental processes like glycolysis, TCA cycle and beta-oxidation. We describe a sex-specific response to Sirt3 loss including maintainance of cellular oxidative status, Hif1a stabilization and induction of Integrated Stress Response (ISR). While female MEFs are significantly more able to tolerate Sirt3 loss, male cells adapt to knock-out by entering a persistent state of cellular stress. Considering many known and potential roles of Sirt3 in metabolism of both normal and cancer cells, aging and longevity, this study emphasizes the crucial role of including sex as a variable in biomedical research.
2024-04-17 | GSE246699 | GEO
Project description: Not available
| S-EPMC8784167 | biostudies-literature
Project description:Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. HIF1A is a major regulator of this process but activation of HIF1A under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of Hypoxia Inducible Factor 1A (HIF1A) transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer. In an attempt to identify the ARRB1 cistrome in prostate cancer cells, C4-2 prostate cancer cells expressing endogenous levels of ARRB1 were used to ChIP for ARRB1, p300 (previously shown to interact with ARRB1within transcriptional complexes), RNA PolII and histone markers H3K4me1 and H4K4me3 (markers for enhancer and promoter regions, respectively). Cells were untreated and cultured in FBS supplemented with 10%FBS. In parallel, C4-2 cells stably expressing a nuclear form of ARRB1 (nucARRB1) were also used to ChIP the same complexes under the same conditions. Finally, human prostate tissue was used to ChIP for ARRB1 and histone markers.
2014-11-26 | E-GEOD-55615 | biostudies-arrayexpress
Project description: Not available
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