HIF1A modulates glycolysis function to governs mouse ovarian microenvironment metabolic plasticity in aging single cell resolution
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201114 | GEO | 2025/04/20
REPOSITORIES: GEO
Similar Datasets
Project description:HIF1A modulates glycolysis function to governs mouse ovarian microenvironment metabolic plasticity in aging single cell resolution
| PRJNA828458 | ENA
Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia inducible factor 1 a (HIF1a) and increased aerobic glycolysis metabolism represent drivers of the development of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1a is activated and how its activity and the subsequent induction of aerobic glycolysis promotes Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1a and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we have identified USP29 as a critical deubiquitylase (DUB) of HIF1a, which directly deubiquitinates and stabilizes HIF1a and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1a is the gene encoding for hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1a transcriptional activity, reduces the levels of aerobic glycolysis and reinstalls the sensitivity to Sorafenib treatment in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1a, USP29 promotes Sorafenib resistance in HCC cells by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.
2021-07-27 | GSE158458 | 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:Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. Here we report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg), and controls cell fate determination. TH17 but not Treg-inducing conditions resulted in strong upregulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1a (HIF1a) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1a-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1a resulted in diminished TH17 development but enhanced Treg differentiation, and protected mice from autoimmune CNS inflammation. Our studies demonstrate that HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. Naïve CD4 T cells from wild-type and HIF1a-deficient mice (in triplicates each group) were differentiated under TH17 conditions for 2.5 days, and RNA was analyzed by microarrays.
2011-06-07 | E-GEOD-29765 | 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:USP29-mediated HIF1a stabilization promotes Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis
| PRJNA665259 | ENA
Project description:The role of HIF1a-glycolysis in regulating IFN-g induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-g is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1a-glycolysis controls IFN-g induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1a in T cells (HIF1a–/–) and glycolytic inhibition significantly abrogate IFN-g induction. Conversely, HIF1a stabilization in T cells by hypoxia and VHL deletion (VHL–/–) promotes IFN-g production. Mechanistically, reduced IFN-g production in hypoxic HIF1a–/– T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1a–/– T cells are less able to kill tumor cells, and HIF1a–/– tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1a in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-g production in hypoxic HIF1a–/– T cells and re-sensitizes HIF1a–/– tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1a-anaerobic glycolysis as a principal mediator of IFN-g induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need
2024-09-24 | GSE253090 | GEO
Project description:Neuroretinal degenerations including retinitis pigmentosa (RP) comprise a heterogeneous collection of pathogenic mutations that ultimately result in blindness. Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, non-cell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.
2025-01-24 | GSE287734 | GEO
Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of prostatic precancerous lesions to malignant tumors provides a broad time-frame for strategies targeting disease emergence. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on prostates of genetically-engineered Pten(i)pe- /- mice. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells during disease progression. Luminal HIF1A enhances glucose metabolism and promotes a PIN-derived secretome that increases the recruitment of myeloid-derived suppressor cells, thus dampening immune surveillance. Moreover, pharmacological inhibition of HIF1A induces apoptosis in early PIN lesions, and slows the proliferation of late ones. Therefore, our study identifies HIF1A as a target for PCa prevention. Importantly, we also demonstrate that HIF1A signaling correlates with the emergence of prostatic luminal cells expressing TGM2, the expression of which predicts early relapse after primary intervention in PCa patients.
2022-06-07 | GSE186419 | GEO
Project description:Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. Here we report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg), and controls cell fate determination. TH17 but not Treg-inducing conditions resulted in strong upregulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1a (HIF1a) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1a-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1a resulted in diminished TH17 development but enhanced Treg differentiation, and protected mice from autoimmune CNS inflammation. Our studies demonstrate that HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
2011-06-07 | GSE29765 | GEO