NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma
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PROVIDER: PRJNA901163 | ENA |
REPOSITORIES: ENA
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Project description:NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma [ChIP-seq]
| PRJNA902015 | ENA
Project description:To explore the differential genes and signaling pathways regulated by NUSAP1 in pancreatic ductal adenocarcinoma, PANC1 cell line was transfected with siRNA or overexpressed plasmid targeted with NUSAP1. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different cells.
2022-11-19 | GSE217873 | GEO
Project description:To explore the genes regulated by Nusap1 protein in pancreatic ductal adenocarcinoma , chromatin immunoprecipitation followed by high-throughput sequencing (CHIP-Seq) were performed in AsPC1 cells.
2022-11-19 | GSE218064 | GEO
Project description:The “Warburg effect” describes the use of aerobic glycolysis by cancer cells to fuel their growth. Lactate dehydrogenase-A (LDHA) is key to this process and catalyzes the interconversion of pyruvate and lactate. Here we used a proteomic approach to identify LDHA as a binding partner of the tumor suppressor FLCN. Canonically, LDHA is thought to be a substrate-regulated enzyme, however our data show that FLCN uncompetitively inhibits LDHA activity by restricting movement of its active site loop. This inhibition appears to be critical in normal cells, as we show FLCN binds to and tightly regulates LDHA activity in order to preserve metabolic homeostasis. Pathogenic mutations of FLCN are associated with LDHA hyperactivity and kidney tumor formation, suggesting a mechanism for FLCN tumor suppressive function. We have identified a cell-permeant ten amino acid peptide based on the FLCN sequence that enters these tumors and inhibits LDHA ex vivo. In a broader context, renal cell carcinomas experience the Warburg effect and show FLCN dissociation from LDHA. Cells that experience this metabolic shift depend on the hyperactivity of LDHA, as previous work has shown attenuation or inhibition of LDHA leads to programmed cell death. Treating these cells with the FLCN-derived peptide causes apoptosis, strongly suggesting that the glycolytic shift of cancer cells is the result of FLCN inactivation or disassociation from LDHA. Taken together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
2021-08-05 | PXD018410 | Pride
Project description:SETDB1, a pivotal histone lysine methyltransferase, has been identified as being transported to the cytoplasm through a CMR1-dependent pathway, contributing to non-histone methylation. However, the function and underlying mechanism of cytoplasmic SETDB1 in breast cancer remain elusive. This study, employing immunohistochemistry, revealed that an elevated level of cytoplasmic SETDB1 is correlated with lymph node metastasis and more aggressive breast cancer subtypes. Functionally, cytoplasmic SETDB1 proves indispensable for cell migration and invasion, as well as the induction of epithelial-mesenchymal transition (EMT), which could be reversed by LMB (a CMR1 inhibitor) treatment. Furthermore, it was observed that cytoplasmic SETDB1 elevates the levels of metabolites associated with the Warburg effect, including glucose, pyruvate, lactate, and ATP. Mechanistically, the release of nuclear SETDB1 alleviates the inhibition of c-MYC transcription, leading to increased c-MYC expression and subsequent up-regulation of LDHA expression. Notably, LDHA overexpression enhanced migration and invasion by inducing EMT, while its depletion can reverse SETDB1-induced migration and invasion, as well as the Warburg effect and EMT. In conclusion, the subcellular localization of cytoplasmic SETDB1 emerges as a pivotal factor in breast cancer progression. This study offers valuable insights into the novel functions and mechanisms of cytoplasmic SETDB1.
2024-03-13 | GSE253717 | GEO
Project description:Histone acetylation involves the transfer of a two-carbon unit to nucleus as embedded in low-concentration metabolites. We find that lactate, a high-concentration metabolic by-product, can be a major carbon source for histone acetylation, through oxidation-dependent metabolism. Both in cells and in purified nucleus, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), the knockout of which abrogates the incorporation. Heterologous expression of nucleus-localized LDHA rescues the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces the acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence of the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing the disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by cell’s own or environmental status.
2023-11-21 | GSE235471 | GEO
Project description:T helper (Th) cell differentiation is driven by antigen and accessory signals that activate phosphoinositide 3-kinase (PI3K) to induce transcriptional and metabolic reprogramming including aerobic glycolysis (the Warburg effect). Here, we show that ATP generated through glycolysis fuels PI3K signaling to promote pathogenic Th17 cell responses. Mice with T cell-specific ablation of the glycolytic enzyme lactate dehydrogenase A (LDHA) were resistant to Th17 cell-mediated experimental autoimmune encephalomyelitis in association with defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled the cellular redox balance and inhibited ATP production causing attenuated phosphoinositide (3,4,5)-trisphosphate generation, and diminished activation of the Akt kinase and phosphorylation of its transcription factor target Foxo1. Th17 cell-specific expression of an Akt-insensitive Foxo1 mutant recapitulated the Th17 cell differentiation defects caused by LDHA deficiency. Thus, PI3K signaling and glycolytic bioenergetics constitute a positive feedback regulatory circuit essential for Th17 cell-mediated autoimmunity.
2021-03-27 | GSE164959 | GEO
Project description:Overexpression of heat shock proteins (HSPs), especially the major stress-inducible 72 kDa heat shock protein 70 (Hsp70), in malignant tumor cells is associated with therapeutic resistance. The heightened metabolic demand in tumor cells (Warburg effect) increases lactate dehydrogenase (LDH) activity and the corresponding increase in lactate concentrations promotes malignancy. Herein, we assessed the co-regulation of LDH and the heat shock response and its link to radiation resistance in B16F10 murine melanoma cells and LS174T human colorectal adenocarcinoma cells. Inhibition of LDHA/B by oxamate or GNE-140, significantly diminishes the expression of Hsp90, Hsp70 and Hsp27 in the cytosol. Diminished expression was also observed in LDHA/B double knockout (LDH-/-) cells. An increased production of reactive oxygen species (ROS) induced by a faster growth rate in wild type (WT) vs LDH-/- cells contributes to increased cytosolic HSP levels in WT cells. LDH-/- cells exhibit a lower density of membrane Hsp70 expression than WT cells and a decreased presence of the tumor-specific, Hsp70 anchoring glycosphingolipid Gb3 on the cell surface which could be attributed to an altered lipid metabolism mediated by the LDH knockout. Functionally, a double knockout of LDHA/B results in a generalized reduction in expression of HSPs in tumor cells and significantly increases radiosensitivity which is associated with a G2/M arrest. In summary, we demonstrate that pharmacological targeting of the lactate/pyruvate metabolism breaks radioresistance by impairing the stress response.
2022-02-17 | PXD026078 | Pride
Project description:LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.
2024-10-18 | PXD056047 | Pride
Project description:Lactate is a major metabolite of tumor cell as a result of Warburg effect. Yet it remains elusive whether and how intracellular lactate may ever drive tumor cell proliferation. To investigat the role of lactate in proliferating cancer cells, we treated HGC27 cells with lactate and then sent for RNA-sequencing analysis.
2024-05-29 | GSE200790 | GEO