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SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE27309 | GEO | 2011/03/15

SECONDARY ACCESSION(S): PRJNA137189

REPOSITORIES: GEO

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SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

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

Transcriptomic analysis of Sirt3 knock-out mouse embryonic fibroblasts reveals major differences in metabolism and stress-response between sexes

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

SIRT3 functions in the nucleus in the control of stress-related gene expression.

Project description:SIRT3 is a member of the Sir2 family of NAD+-dependent protein deacetylases that promotes longevity in many organisms. The processed, short form of SIRT3 is a well-established mitochondrial protein whose deacetylase activity regulates various metabolic processes. However, the presence of full-length (FL) SIRT3 in the nucleus and its functional importance remains controversial. Our previous studies demonstrated that nuclear FL-SIRT3 functions as a histone deacetylase and is transcriptionally repressive when artificially recruited to a reporter gene. Here, we report that nuclear FL-SIRT3 is subjected to rapid degradation upon cellular stress, including oxidative stress and UV-irradiation, whereas the mitochondrial, processed form is unaffected. FL-SIRT3 degradation is mediated by the ubiquitin-proteasome pathway, at least partially through the E3 activity of SKP2. Finally, we show by chromatin immunoprecipitation that some target genes of nuclear SIRT3 are derepressed upon the degradation of SIRT3 caused by stress stimuli. Thus, SIRT3 exhibits a previously unappreciated role in the nucleus modulating the expression of some stress-related and nuclear-encoded mitochondrial genes. ChIP-seq with a SIRT3 antibody in untreated, UV-irradiated, and stable SIRT3 knockdown (KD) U2OS cells

2012-10-16 | E-GEOD-41000 | biostudies-arrayexpress

Expression data from mice lacking SIRT3 under dietary stress

Project description:SIRT3 is a mitochondrial NAD(+)-dependent protein deacetylase, which regulates the enzymatic activity of several mitochondrial proteins. We used microarrays to identify the differences in gene expression as a result of loss of SIRT3, under standard and high-fat diet conditions Wild-type and SIRT3KO mice were sacrificed at 12weeks of age and RNA was extracted from liver tissue, and hybridized on Affymetrix microarrays, to determine differences in gene expression as a result of diet

2011-07-11 | E-GEOD-30552 | biostudies-arrayexpress

Expression data from mice lacking SIRT3 under dietary stress

2011-07-11 | GSE30552 | GEO

Global knock out of Sirt3 gene in Alzheimer’s transgenic mice with amyloid pathology

Project description:We have previously demonstrated that Sirt3 gene deletion, a model for metabolic syndrome, leads to brain mitochondrial dysfunction and neuroinflammation. We also reported that silencing of Sirt3 gene in APP/PS1 mice results in exacerbation of insulin resistance, neuroinflammation and β amyloid plaque deposition. To further understand how metabolic syndrome and amyloid pathology interact, we performed RNA-seq analysis of the brain samples from wild type, Sirt3-/- , APP/PS1 and APP/PS1/Sirt3-/- mice.

2022-10-24 | GSE216081 | GEO

SIRT3 functions in the nucleus in the control of stress-related gene expression.

2012-10-16 | GSE41000 | GEO

Non-oncogene addiction to SIRT3 plays a critical role in lymphomagenesis

Project description:Diffuse large B-cell lymphomas (DLBCLs) are genetically heterogeneous and highly proliferative neoplasms derived from germinal center (GC) B-cells. Herein, we show that DLBCLs are dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B-cell lymphomagenesis in VavP-Bcl2 mice without affecting normal GC formation. Mechanistically, SIRT3 depletion impaired glutamine flux to the TCA cycle via glutamate dehydrogenase and reduction in acetyl-CoA pools, which in turn induce autophagy and cell death. We developed a mitochondrial-targeted Class I sirtuin inhibitor, YC8-02, that phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs.

2019-10-08 | GSE130751 | GEO

Combinatorial targeting of glycolysis and oxidative phosphorylation suppresses tumor growth and metastases.

Project description:The Warburg effect, consisting of increased glucose uptake and glycolysis, provides metabolic energy as well as cellular building blocks for tumor growth. Inhibition of the Warburg effect with 2-deoxyglucose (2DG) has been explored in clinical trials with limited efficacy. Blockage of glycolysis can induce autopahgy resulting in alternative energy generation through oxidative phosphorylation providing a potential bypass of the effects of inhibition of glycolysis. Here in we demonstrate that activation of AMPK, as a consequence of energetic stress, induces mitochondrial energy production potentially bypassing the effects of glycolysis inhibition. We thus combined blockage of glycolysis by 2DG with inhibition of the electron transfer complex I (ETC1) in the mitochondria with the clinically applicable antidiabetic drug metformin. The combination resulted in activation of AMPK and autopahgy that however rendered eventual depletion of ATP and cell death. Furthermore, combined inhibition of glycolysis and mitochondrial respiration inhibited tumor growth and markedly decreased metastatic capacity in vivo. In order to understand the mechanism of these metabolic inhibitors, we performed whole genome transcriptional analysis. Human SK-4 esophageal cancer cell lines were treated with 5 different treatment groups [2 deoxy glucose (4mM), Metformin (5mM), AICAR (2mM), 2 deoxy glucose (4mM) plus Metformin (5mM) and 2 deoxy glucose (4mM) plus AICAR (2mM)] with non treated control groups for 12 hrs. Each groups was quadruplicated. Microarray experiments and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)

2012-12-31 | E-GEOD-16816 | biostudies-arrayexpress

The SIRT3-DsbA-L-TFAM Axis Suppresses Liver cGAS Signaling and MASH Progression in Male Mice

Project description:While mitochondrial dysfunction is implicated in metabolic dysfunction associated steatohepatitis (MASH), the precise underlying mechanisms remain obscure. Here, we identify the SIRT3-DsbA-L-TFAM axis as a crucial suppressor for mitochondrial stress-induced cGAS activation in the hepatocytes, thereby alleviating MASH in mice. SIRT3 facilitates the deacetylation of Disulfide-bond-A oxidoreductase-like protein (DsbA-L) at lysine residues (Lys165, Lys167, and Lys177), which promotes the interaction between DsbA-L and mitochondrial transcription factor A (TFAM), essential for the preservation of mitochondrial integrity and function. Hepatocyte-specific knockout of SIRT3 or DsbA-L in male mice promoted mitochondrial DNA release into the cytosol, resulting in activation of the cGAS-STING pathway and exacerbation of MASH characteristics. Conversely, hepatocyte-specific knockout of cGAS or overexpression of DsbA-L mitigated diet- and SIRT3 deficiency-induced MASH progression. Our study underscores the clinical significance of targeting SIRT3 and cGAS as pivotal therapeutic avenues to inhibit the progression of MASH.

2024-11-30 | GSE281667 | GEO

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