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Project description:SIRT3, a therapeutic target in DLBCL
| PRJNA606900 | ENA
Project description:Cancer cells frequently hijack adaptive stress response signals/pathways to protect themselves from metabolic or genetic vulnerabilities, pointing to candidate therapeutic targets. Among these SIRT3 was recently identified as a non-oncogene addiction mechanism in DLBCL through its role in glutamine metabolism. Here, we investigated downstream signaling pathways linked to SIRT3 function in lymphoma. We performed RNA-seq in DLBCL cells after SIRT3 knockdown and observed that ATF4 target genes were significantly downregulated in SIRT3 deficient cells. ATF4, a master regulator of cellular stress, was required to maintain proliferation and survival of DLBCL cells and its target genes were overexpressed in DLBCL patients as compared to normal germinal center B cells. Translation of ATF4 mRNA was inhibited in SIRT3 knockdown cells and expression of exogenous ATF4 partially rescued cell proliferation and viability inhibited by SIRT3 deficiency. Accordingly, ATF4 protein was expressed at relatively lower levels SIRT3 deficient murine lymphomas, whereas its higher expression was associated with more severe disease. We characterized mechanisms through which SIRT3 maintains ATF4 expression, downstream of its effects on glutamine entry into the TCA cycle and suppression of autophagy. Specifically, loss of SIRT3 disrupted amino acid metabolism in DLBCL cells, with subsequent impairment of ATF4 response to metabolic stressors such as glutamine depletion. Collectively, the data suggest a key SIRT3-ATF4 axis maintains survival of DLBCL cells enabling them to optimize amino acid metabolism and cope with metabolic vulnerabilities possibly associated with their high proliferative rate.
2022-09-20 | GSE158833 | 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. 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: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
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.
2012-10-16 | GSE41000 | GEO
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.
2022-08-17 | GSE179617 | GEO
Project description:Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with critical roles in the normal development and malignant transformation of lymphocytes. Recently we have shown that plasma cell cancers (multiple myeloma, MM) are addicted to an aberrant gene expression program ochestrated by wild-type IRF4 for their survival. Here we show that an aggressive malignancy of mature B cells, the activated B cell for of Diffuse Large B Cell lymphoma (ABC-DLBC), also depends on IRF4 for survival. With genome-wide expression profiling and localization (ChIP-Seq) assays, we identified IRF4 target genes in ABC-DLBCL as members of diverse pathways related to B cell biology and malignant behavior, distinct from IRF4 targets in MM. For example, we find the gene encoding the NFkB signal transduction adapter protein CARD11 is a target of IRF4 activation, driving the critical NFkB pathway in ABC-DLBCL. Further, we find enrichment of DNA binding motifs for ETS-IRF factors in regions of IRF4 binding in ABC-DLBCL suggesting cooperative activity between IRF4 and an ETS family transcription factor. Through complementation assays we show that IRF4 and the critical ABC-DLBCL ETS factor SPIB interact with one another and are key to ABC-DLBCL survival. Together our data show that ABC-DLBCL is addicted to the interaction between IRF4 and SPIB, in part through a positive feedback loop invovling CARD11 and the activation of the NFkB pathway. These data suggest theraepeutic potential in targeting the IRF4:SPIB interface in ABC-DLBCL.
2011-07-01 | GSE22901 | GEO
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