Small molecule screen identifies de novo nucleotide synthesis as a vulnerability of cells lacking SIRT3
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ABSTRACT:
PROVIDER: PRJNA430334 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6496520_1.fastq.gz | Fastqsanger.gz | |||
| SRR6496520_2.fastq.gz | Fastqsanger.gz | |||
| SRR6496521_1.fastq.gz | Fastqsanger.gz | |||
| SRR6496521_2.fastq.gz | Fastqsanger.gz | |||
| SRR6496522_1.fastq.gz | Fastqsanger.gz |
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Project description:Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration, and high fat diet (HFD)-induced metabolic disorders. Thus, we performed a small molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss.
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Project description:Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells. Furthermore, we found that SIRT3 KO cells upregulated the diversion of glutamine into de novo nucleotide synthesis through hyperactive mTORC1 signaling. Overexpression of SIRT3 suppressed mTORC1 and growth in vivo in a xenograft tumor model of breast cancer. Thus, we have uncovered a metabolic vulnerability of cells with SIRT3 loss by using an unbiased small-molecule screen.
| S-EPMC5902027 | biostudies-literature
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
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
2011-07-11 | GSE30552 | GEO
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: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
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: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.
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Project description:SIRT3 deacetylase is a critical mitochondrial regulator for mitochondrial metabolism reprogramming and ROS production, and is involved in the regulation of chemoresistance in AML. SIRT3 is a SUMOylated protein, with de-SUMOylation by SENP1, resulted in enhancement of its deacetylase activity. However, the molecular mechanism of de-SUMOylation mediated SIRT3 activation, which may lead to reinforced AML chemoresistance, remains poorly understood. In the current study, we demonstrated that SIRT3 SUMOylation was attenuated by cytarabine, and de-SUMOylation prevented SIRT3 from proteasome degradation. SIRT3 de-SUMOylation was capable of reprogramming mitochondrial biogenesis, and subsequently inhibited mitochondrial ROS production. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation, among which the transcription factor HES1, a downstream substrates of Notch1 signaling pathway, was significantly downregulated by SIRT3K288R, the de-SUMOylated and constitutively active mutant of SIRT3. HES1-dependent FAO was inhibited by SIRT3 de-SUMOylation. Moreover, cytarabine synergized with the SENP1 inhibitor momodrin-Ic to eradicate AML blasts in vitro and in xenografts mice models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in regulating chemoresistance in AML via HES1-dependent FAO, which may provide a rationale for SIRT3 SUMOylation-targeted intervention to improve the chemotherapies in AML.
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