O-GlcNAc transferase promotes glioblastoma through genes responsible for cell survival, invasion and inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE234473 | GEO | 2023/10/23
REPOSITORIES: GEO
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Project description:O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease.To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGTLKO) were generated.Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress- induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8- week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis.
2024-03-12 | GSE261136 | GEO
Project description:Dysfunctional mitochondria and generation of reactive oxygen species (ROS) promote chronic diseases, which have spurred interest in the molecular mechanisms underlying these conditions. Previously, we have demonstrated that disruption of post-translational modification of proteins with β-linked N-acetylglucosamine (O- glcnAcylation) via overexpression of the O-glcnAc–regulating enzymes O- glcnAc transferase (OGT) or O- glcnAcase (OGA) impairs mitochondrial function. Here, we report that sustained alterations in O- glcnAcylation either by pharmacological or genetic manipulation also alters metabolic function. Sustained O-glcnAc elevation in SH-SY5Y neuroblastoma cells increased OGA expression and reduced cellular respiration and ROS generation. Cells with elevated O-glcnAc levels had elongated mitochondria and increased mitochondrial membrane potential, and RNA-Seq in SH-SY5Y cells indicated transcriptome reprogramming and down regulation of the NRF2-mediated antioxidant response. Sustained O-glcnAcylation in mice brain and liver validated the metabolic phenotypes observed in the cells, and OGT knockdown in the liver elevated ROS levels, impaired respiration, and increased the NRF2 antioxidant response. Moreover, elevated O-glcnAc levels promoted weight loss and lowered respiration in mice and skewed the mice toward carbohydrate-dependent metabolism as determined by indirect calorimetry. In summary, sustained elevation in O-glcnAcylation coupled with increased OGA expression reprograms energy metabolism, a finding that has potential implications for the etiology, development, and management of metabolic diseases.
2017-07-20 | GSE101642 | GEO
Project description:O-GlcNAcylation is the modification of serine and threonine residues with beta-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. To investigate the role of protein O-GlcNAcylation on intestinal homeostasis, we generated intestinal epithelial cell (IEC)-specific O-GlcNAc transferase (OGT) knockout in mice. The KO mice developed spontanous intestinal inflammation. To determine the underlying molecular mechanisms, we performed RNA sequencing of ileum and colon epithelial cells of wildtype and IEC-OGT KO mice.
2017-06-27 | GSE100473 | GEO
Project description:The reversible posttranslational O-GlcNAc modification of serine or threonine residues of intracellular proteins is involved in many cellular events from signaling cascades to epigenetic and transcriptional regulation. O-GlcNAcylation is a conserved nutrient-dependent process involving two enzymes, O-GlcNAc Transferase (OGT) adding O-GlcNAc while O-GlcNAcase (OGA) removing it in a manner that’s protein and context dependent. O-GlcNAcylation is essential for epigenetic regulation of gene expression through its action on Polycomb and Trithorax and Compass complexes. However, the important role of O-GlcNAc on adult life and healthspan have been largely unexplored, mainly due the lack of available model systems. Cataloging the O-GlcNAc proteome has proven useful in understanding the biology of this modification in vivo. In this study, we leveraged a recently developed oga knockout fly mutant to identify the O-GlcNAcylated proteins in adult Drosophila melanogaster. The adult O-GlcNAc proteome revealed many proteins related to cell and organismal growth, development, differentiation, and epigenetics. We identified many O-GlcNAcylated proteins that serve a role in increased growth and decreased longevity, including HCF, SIN3A, LOLA, KISMET, ATX2, SHOT, and FOXO.
2021-04-26 | PXD025344 | Pride
Project description:Every year, about 18 million babies are born from mothers with gestational diabetes mellitus (GDM). While diabetic symptoms usually resolve after delivery, lasting complications can occur for both mother and child, including fetal overgrowth, type 2 diabetes (T2D), cardiovascular diseases, and obesity. The rapid progression of GDM is unique to pregnancies, and likely arises from placental dysfunction. Indeed, stress, nutrition and fetal gender are thought to trigger changes in placental endocrine function, including metabolic hormones and inflammatory cytokines, potentially causing GDM. Nutrient-sensing O-GlcNAcylation and its enzyme O-GlcNAc Transferase (OGT, X-linked) has been previously identified as a placental biomarker of maternal stress particularly deleterious for male offspring. Thus, we wondered whether O-GlcNAcylation participate in GDM development in a sex-dependent manner. After demonstrating that OGT is largely downregulated in male GDM compared to healthy placentas, we knocked down OGT in male trophoblastic cells. We observed changes in placental hormones, cytokines and nutrient-sensing pathways, correlating with previously demonstrated disruption in GDM placentas. Altogether, this study demonstrates that OGT and O-GlcNAcylation are partly responsible for changes observed in GDM placenta and might be the cause of sexual dimorphism observed in this pathology.
2022-04-21 | GSE200983 | GEO
Project description:EGF is one of the most well-characterized growth factors and plays a crucial role in cell proliferation and differentiation. EGFR has been extensively explored as a therapeutic target against multiple types of cancers, such as lung cancer and glioblastoma. Recent studies have established a connection between deregulated EGF signaling and metabolic reprogramming, especially rewiring in aerobic glycolysis, which is also known as the Warburg effect and recognized as a hallmark in cancer. Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme controlling the final step of glycolysis and serves as a major regulator of the Warburg effect. We previously showed that PKM2 T405/S406 O-GlcNAcylation, a critical mark important for PKM2 detetramerization and activity, was markedly upregulated by EGF. However, the mechanism by which EGF regulates PKM2 O-GlcNAcylation still remains uncharacterized. Here we demonstrated that EGF promoted O-GlcNAc transferase (OGT) binding to PKM2 by stimulating OGT Y976 phosphorylation. As a consequence, PKM2 O-GlcNAcylation and detetramerization were upregulated, leading to a significant decrease in PKM2 activity. Moreover, other than PKM2, the association of additional phosphotyrosine binding proteins, including STAT1, STAT3, STAT5, PKCδ and p85, which are reported factors bearing O-GlcNAcylation, with OGT was also enhanced when Y976 was phosphorylated. Together, EGF-dependent Y976 phosphorylation is critical for OGT-PKM2 interaction and we propose that this post-translational modification might be important for the substrate selection by OGT.
2022-08-22 | PXD031593 | Pride
Project description:The addition of O-GlcNAc (a single β-D-N-acetylglucosamine sugar at serine and threonine residues) by O-GlcNAc transferase (OGT) and removal by O-GlcNAcase (OGA) maintains homeostatic levels of O-GlcNAc. We investigated the role of OGlcNAc homeostasis in hematopoiesis utilizing G1E-ER4 cells carrying a GATA-1 transcription factor fused to the estrogen receptor (GATA-1ER) that undergo erythropoiesis following the addition of β-estradiol (E2) and myeloid leukemia cells that differentiate into neutrophils in the presence of all-trans retinoic acid. During G1E-ER4 differentiation, a decrease in overall O-GlcNAc levels and an increase in GATA-1 interactions with OGT and OGA were observed. Transcriptome analysis on G1E-ER4 cells differentiated in the presence of Thiamet-G (TMG), an OGA inhibitor, identified expression changes in 433 GATA-1 target genes. Chromatin immunoprecipitation demonstrated that the occupancy of GATA-1, OGT, and OGA at Laptm5 gene GATA site was decreased with TMG. Myeloid leukemia cells showed a decline in O-GlcNAc levels during differentiation and TMG reduced the expression of genes involved in differentiation. Sustained treatment with TMG in G1E-ER4 cells prior to differentiation caused a reduction of hemoglobin positive cells during differentiation. Our results show that alterations in O-GlcNAc homeostasis disrupt transcriptional programs causing differentiation errors suggesting a vital role of O-GlcNAcylation in control of cell fate.
2018-11-06 | GSE122104 | GEO
Project description:We report that cellular O-GlcNAcylation levels decline along the course of megakaryocyte (MK) differentiation from human-derived hematopoietic stem and progenitor cells (HSPCs) and that inhibition of O-GlcNAc transferase (OGT), of which catalyzes O-GlcNAcylation, prolongedly decreases O-GlcNAcylation and induces megakaryopoiesis and thrombopoiesis. To gain the better insight into the potential mechanisms underlying platelet regulation by O-GlcNAcylation ,we compared the genome-wide transcription profiles of megakaryblastic MEG-01 cells with decreased O-GlcNAcylation (OGTi) and its control counterpart using RNA sequencing. Gene ontology and enrichment analysis of differentially expressed genes suggest that platelet formation might be regulated through the perturbation in cell adhesion molecules, i.e. integrin-a4 and b7, downstream of O-GlcNAc/c-Myc axis.
2020-08-06 | GSE150880 | GEO
Project description:The hexosamine biosynthetic pathway (HBP) is a pathway that requires glucose using approximately 3% ~ 5% of total glucose coming into cells. HBP synthesizes UDP-GlcNAc using not only glucose but also various metabolic products such as those amino acid, fatty acid and nucleotide. O-GlcNAcylation by Ogt is considered the act as a nutrient sensor because the amount of UDP-GlcNAc is influenced by various metabolites. Therefore, when the balance of O-glcnacylation is broken, it induces diseases such as cancer or neurological diseases or affects the differentiation of cells. Bone homeostasis is regulated by osteoblasts that produce bone and osteoclasts that resorb bone. Disruption of this balance leads to diseases such as osteoporosis. Previous studies reported that osteoblast differentiation was inhibited by excessive O-GlcNAcylation. Increased o-glcnacylation of runx2 induced bone homeostasis imbalance by reducing the transcriptional activity of runx2 and mRNA expression of the target gene of runx2 involved in osteoblast differentiation. However, how O-GlcNAcylation regulates differentiation of osteoclast remains unclear. So, the goals of our study are to describe expression changes in genes expression associated with O-GlcNAcylation during RNAKL-mediated osteoclast differentiation.
2021-06-08 | GSE176265 | GEO
Project description:O-GlcNAcylation occurs on thousands of proteins involved in various cellular events. O-GlcNAc transferase (OGT), one of the enzymes responsible for protein O-GlcNAcylation, is known to be auto-O-GlcNAcylated at multiple sites. However, the role of O-GlcNAcylation on OGT is still unknown. Here, we report the role of O-GlcNAcylation on short form OGT (sOGT). By LC-ETD-MS analysis and western blot, we show that sOGT was mainly O-GlcNAcylated in the tetratricopeptide repeat (TPR) motifs with T12 and S56 being two “key” sites. T12 was a predominant O-GlcNAcylation site and the absence of S56 O-GlcNAcylation enhanced sOGT O-GlcNAcylation level. We found that O-GlcNAcylation of sOGT did not affect the enzyme activity but increased its binding to substrate proteins. S56A bound to and hence glycosylated more proteins, while T12A associated with fewer substrates. Proteomic studies combined with cell proliferation/cell cycle analyses indicated that S56A substantially enhanced cell proliferation, while T12A reduced it, and T12A led to a G2/M cell cycle arrest, due to O-GlcNAcylation of diverse proteins. These findings demonstrate that the O-GlcNAc pattern on sOGT modulates its function in cells by targeting different proteins.
2019-09-16 | PXD009731 | Pride