RFX6 facilitates aerobic glycolysis-mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1
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ABSTRACT:
PROVIDER: PRJNA1041559 | ENA |
REPOSITORIES: ENA
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Project description:Background: Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous. Methods: Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumor and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation (ChIP), untargeted metabolome profiling, and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings. Results: HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of PGAM1 and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC. Conclusions: RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting.
2023-12-20 | GSE248063 | GEO
Project description:Background: Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous. Methods: Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumor and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation (ChIP), untargeted metabolome profiling, and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings. Results: HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of PGAM1 and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC. Conclusions: RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting.
2023-12-20 | GSE248062 | GEO
Project description:RFX6 facilitates aerobic glycolysis-mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1 [ChIP-Seq]
| PRJNA1041561 | ENA
Project description:RFX6 facilitates aerobic glycolysis-mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1 [RNA-Seq]
| PRJNA1041562 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-12-20 | GSE248064 | GEO
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: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:This study provides evidence on the molecular mechanisms by which P2RX7 signaling promotes Th1 cell differentiation. P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-polarized CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, ATP synthase blockade in vitro and the consequent inhibition of oxidative phosphorylation, which forces cells to use aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 cell differentiation and suggest that ATP synthase inhibition is a fundamental mechanism by which P2X7 signaling induces the Th1 response.
2023-03-08 | PXD037754 | Pride
Project description:Osteosarcoma (OS) is the most common primary malignant neoplasm of the bone. Recent studies have indicated that the inhibitory effects of microRNA (miR)-324-3p could affect the development of numerous cancers. However, its biological roles and underlying mechanisms in OS progression remain unexplored. In this study, miR-324-3p expression was markedly reduced in OS cell lines and tissues. Functionally, miR-324-3p overexpression suppressed OS progression and was involved in the Warburg effect. Mechanistically, miR-324-3p negatively regulated phosphoglycerate mutase 1 (PGAM1) expression by targeting its 3'-UTR. Moreover, high expression of PGAM1 promoted OS progression and aerobic glycolysis, which were associated with inferior overall survival in patients with OS. Notably, the tumor suppressor functions of miR-324-3p were partially recovered by PGAM1 overexpression. In summary, the miR-324-3p/PGAM1 axis plays an important role in regulating OS progression by controlling the Warburg effect. Our results provide mechanistic insights into the function of miR-324-3p in glucose metabolism and subsequently on the progression of OS. Targeting the miR-324-3p/PGAM1 axis could be a promising molecular strategy for the treatment of OS.
| S-EPMC10236611 | biostudies-literature