ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism
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ABSTRACT:
PROVIDER: PRJNA761712 | ENA |
REPOSITORIES: ENA
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Project description:Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.
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Project description:The essential roles of PCNA as a scaffold protein in DNA replication and repair are well established, while its more recently discovered cytosolic roles are less explored. Alpha-enolase (ENO1) and 6-phosphogluconate dehydrogenase (6PGD), important proteins in glycolysis and the Pentose Phosphate Pathway (PPP), respectively, both contain PCNA interacting motifs. Here we show reduced binding to PCNA when the PCNA interacting motif APIM in ENO1 is mutated. Mutant cells have lower ENO1 protein levels, have reduced glucose consumption, altered glycolytic metabolite and nucleoside phosphate pools and increased activation of the citric acid cycle (TCA) compared to parental cells. Treatment of a panel of haematological cell lines with a cell penetrating peptide containing APIM (ATX-101), lead to a metabolic shift with reduction in glycolytic metabolite and nucleoside phosphate pools as well reduced levels of ENO1 and 6PGD proteins. These results suggests that PCNA stabilize ENO1 and 6PGD, and that targeting PCNA reduce the glycolysis, PPP and nucleoside phosphate pools via destabilization of these proteins.
2023-03-10 | PXD028314 | Pride
Project description:HeLa cells were either treated with ENO1 or control siRNAs using the protocol of the RNAiMax reagent (ENO1 pool: SMARTpool ON-TARGETplus L-004034-00-0005 and control pool: ON-TARGETplus non-targeting siRNAs 1-4). Three replicates per condition were produced.
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Project description:Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here show that these two pathways appear to be functionally connected via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Targeting this intersection with oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death.
2024-05-29 | GSE239431 | GEO
Project description:Free fatty acids play an important role during infection by modulating immune responses, but also by directly functioning as antimicrobials. Particularly, the host’s long chain polyunsaturated fatty acids, not commonly found in bacterial pathogens, have significant antibacterial potential. Of these arachidonic acid (AA) is in high abundance, and in this study we show that upon infection with the Streptococcus pneumoniae the AA concentration in the blood increases. Hence, we investigated the transcriptmoic effects of AA on this extremely problematic bacterial pathogen.
2018-05-23 | GSE93102 | GEO
Project description:ENO1 (α-Enolase 1) is a key glycolytic enzyme that catalyzes the dehydratation of 2-phosphoglycerate to phosphoenolpyruvate. It also belongs to a member of the RNA degradosome of Escherichia coli and facilitates RNA degradation, but it’s currently unknown whether ENO1 possesses similar function in eukaryotes. To test this possibility,we performed RNA-seq assays expressing NTC or ENO1 shRNA, respectively.
2021-09-10 | GSE153989 | GEO
Project description:Yangyinqingfei Decoction (YYQFD), a traditional Chinese prescription, is well known in the treatment of diphtheria and lung-related diseases in clinic. However, the underlying mechanism how to treat lung-related diseases remains unclear. In the present study, the intervention effect of YYQFD on PM2.5-induced lung injury mice and its potential mechanism were investigated by metabolomics and proteomic techniques. The results showed that YYQFD could significantly improve pulmonary functions, relieve lung injury, as well as reduce IL-6, TNF-α and MDA, and increase SOD levels in serum and BALF of PM2.5-induced lung injury mice. Furthermore, the protein-metabolite joint analysis presented that YYQFD regulated the pathways of arachidonic acid metabolism, linoleic acid metabolism, and biosynthesis of unsaturated fatty acids with significantly down-regulating arachidonic acid, 20-HETE, prostaglandin E2, lecithin, linoleic acid, α-linolenic acid, eicosatetraenoic acid, and γ-linolenic acid, and up-regulating PTGES2, GPX2 and CBR3 protein expressions in lung tissue. A regulatory metabolic network map was further constructed, which provide us a better understanding about the role of YYQFD on PM2.5-induced lung injury mice and new insight into YYQFD application for the treatment of lung-related diseases.
2022-12-22 | PXD037163 | Pride
Project description:The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Its dysregulation has been well-studied to promote tumor initiation and progression, including gastric cancer (GC). Although the Hippo-YAP1 signaling pathway regulates the expression of thousands of target genes, how these target genes contribute to the oncogenic program driven by YAP1 remains unknown. Here we identified the vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Knocking down FOXP4 impairs GC spheroid formation and inhibits stemness marker expression, while its upregulation potentiates the cancer cells with more stemness. RNA-seq analysis revealed SOX12 as functional downstream of FOXP4 in the YAP1-induced carcinogenesis. Targeting FOXP4 by 42-(2-Tetrazolyl) rapamycin in GC cells enhanced the 5-FU efficacies. Our findings have unveiled FOXP4 as a novel stemness marker that promotes tumorigenesis by upregulating SOX12. Additionally, we have identified FOXP4 as a direct target for modulating YAP1 signaling in GC. Therefore, the YAP1-FOXP4-SOX12 axis presents a promising therapeutic target for GC.
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