SMYD3 promotes aerobic glycolysis in diffuse large B-cell lymphoma via H3K4me3-mediated PKM2 transcription
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ABSTRACT:
PROVIDER: PRJNA854584 | ENA |
REPOSITORIES: ENA
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Project description:Genetic abnormalities in histone methyltransferases (HMTs) frequently occur in diffuse large B-cell lymphoma (DLBCL) and are related to its progression. SET and MYND domain containing 3 (SMYD3) is an HMT that is upregulated in various tumors and promotes their malignancy. To further explore the functional role of SMYD3 in DLBCL, RNA-Seq was carried out on total RNA isolated from SMYD3-knockdown or control OCI-LY8 cells.
2022-07-03 | GSE207262 | GEO
Project description:Different distribution of PKM2 drives neurons to use aerobic glycolysis in somata to prevent oxidative damage and OXPHOS in terminals to meet high energy demands.
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2018-10-24 | PXD007671 | Pride
Project description:Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions.
2021-07-30 | MTBLS533 | MetaboLights
Project description:Phosphoglycerate mutase 1 (PGAM1) is a key-node enzyme that diverts the metabolic intermediates from glycolysis into its shunts to support macromolecule biosynthesis for rapid and sustainable cell proliferation. It is prevalent that PGAM1 activity is upregulated in various tumors; however, the underlying mechanism remains unclear. Here, we unveil that pyruvate kinase M2 (PKM2) moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, that is essential for PGAM1 activity. Moreover, the dimeric or monomeric PKM2 in tumor cells phosphorylates PGAM1 more efficiently than the tetrameric one. In response to epidermal growth factor (EGF), Src signaling triggered PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and the subsequent H11 phosphorylation of PGAM1, which constitutes the discrepancy between tumor cells and normal ones. A PGAM1-derived pY119-containing cell-permeable peptide or Y119 mutation disrupts the interaction of PGAM1 with PKM2 and its H11 phosphorylation, and eventually dampens the glycolysis shunts and tumor growth. We not only identifes a histidine kinase function of PKM2, but also illustrates an enzymes-cross-talk regulatory mode during metabolic reprogramming.
2024-03-21 | PXD049235 | Pride
Project description:Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 controls macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. These results show that TEPP-46, an activator of PKM2, reduces CD4+ T cell activation, proliferation, and cytokine production by inhibiting essential signaling pathways and preventing glycolysis.
2019-11-26 | GSE139378 | GEO
Project description:Purpose: PKM2-mediated metabolic switch to aerobic glycolysis plays a critical role in promoting cell survival and proliferation. However, little is known about the function of intestinal epithelial PKM2 in intestinal homeostasis. Here we investigated whether and how intestinal epithelial PKM2 modulates the morphology and function of the adult intestine in experimental murine colitis. Methods: Colonoscopic biopsies from the Crohn’s disease (CD) and ulcerative colitis (UC) patients (10 each) were analyzed for PKM2 expression. We also generated intestinal epithelial-specific Pkm2 knockout mice and employed them to examine PKM2 function. Mouse intestinal inflammation was induced with dextran sulfate sodium (DSS) in drinking water. Disease phenotypes were investigated by mouse survival, body weight, colon length and analysis of immune cell infiltration in colon, intestinal epithelial cell gene profiling and signal pathway. Results: Intestinal epithelial PKM2 level in UC and CD patients was significantly decreased compared to that from non-inflamed intestinal epithelium. Similar reduction of intestinal epithelial PKM2 was observed in mice with experimental colitis. Supporting the notion that PKM2 serves as a safeguard against colitis, intestinal epithelial-specific Pkm2-deficient (Pkm2-/-) mice displayed a severer intestinal inflammation, companying with shortened colon, disruption of epithelial tight junction, higher permeability, elevation of inflammatory cytokines and immune cell infiltration, compared with wild-type mice. Gene profiling and western blot analysis indicated that cell survival signaling, particularly the Akt/β-catenin pathways, were downregulated in Pkm2-/- mice. Functional assay using mouse primary colonic epithelial cells confirmed that Pkm2 reduction decreased proliferation and migration of epithelial cells, while enhanced expression of Pkm2 was associated with increased transcriptional activity of β-catenin. Moreover, increasing mouse intestinal epithelial Pkm2 expression via delivery of Pkm2-expressing plasmid attenuated DSS-induced experimental colitis. Conclusions: Intestinal epithelial PKM2, through activating Wnt/β-catenin signaling, induces a strong proliferative and migratory response that increases cell survival and wound healing under colitic condition.
2018-08-20 | GSE118732 | GEO
Project description:Phosphoglycerate mutase 1 (PGAM1) is a key node enzyme that diverts the metabolic reactions from glycolysis into its shunts to support macromolecule biosynthesis for rapid and sustainable cell proliferation. It is prevalent that PGAM1 activity is upregulated in various tumors; however, the underlying mechanism remains unclear. Here, we unveil that pyruvate kinase M2 (PKM2) moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, that is essential for PGAM1 activity. Moreover, monomeric and dimeric PKM2 are efficient to phosphorylate and activate PGAM1, while the tetrameric PKM2 is not. In response to epidermal growth factor (EGF) signaling, Src-catalyzed PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and the subsequent PGAM1 H11 phosphorylation, which constitutes the discrepancy between tumor cells and normal ones. A PGAM1-derived pY119-containing cell-permeable peptide or Y119 mutation disrupted the interaction of PGAM1 with PKM2 and its H11 phosphorylation, and eventually dampened the glycolysis shunts and tumor growth. We not only identified a function of PKM2 as a histidine kinase, but also illustrated an enzymes-cross-talk regulatory mode during metabolic reprogramming.
2024-03-21 | PXD049310 | Pride
Project description:Understanding the mechanisms of the Warburg shift to aerobic glycolysis is central to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by bi-allelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed of the mitochondrial in tumors from HLRCC patients. Biochemical and transcriptomics analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of expression of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
2021-01-22 | GSE157256 | 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