FBXW7 Mutations Reprograms Glucose Metabolism by Activating the ETV6-GLUT Axis in Endometrial Cancer
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ABSTRACT:
PROVIDER: PRJNA1221866 | ENA |
REPOSITORIES: ENA
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Project description:Endometrial cancer (EC) is associated with metabolic reprogramming, driven in part by mutations in FBXW7, a key tumor suppressor. In this study, we reveal that FBXW7 regulates glucose metabolism by targeting ETV6 for ubiquitination and proteasomal degradation. Loss of FBXW7 leads to ETV6 stabilization, which in turn upregulates GLUT1 expression and promotes its localization to the plasma membrane. This enhances glucose uptake and reprograms cellular metabolism toward increased aerobic glycolysis and oxidative phosphorylation. Functional studies demonstrate that ETV6 overexpression accelerates EC cell proliferation, colony formation, and tumor growth in vitro and in vivo, effects that are significantly attenuated by pharmacological inhibition or genetic knockdown of GLUT1. Mechanistically, ETV6 directly binds to the GLUT1 promoter via its ETS and PNT domains, driving its transcriptional activation. Furthermore, metabolomics analyses reveal alterations in glycolytic and TCA cycle intermediates, highlighting the broad impact of the FBXW7-ETV6-GLUT1 axis on metabolic pathways. These findings establish ETV6 as a central mediator of FBXW7-deficiency-driven metabolic reprogramming and tumor progression in EC. Targeting GLUT1 provides a potential therapeutic strategy to mitigate ETV6-induced tumor growth and metabolic remodeling in endometrial cancer.
2025-02-11 | GSE289181 | GEO
Project description:To determine the protein partners of ETV6, we expressed ETV6 and HA-tagged ETV6 in Reh pre-B leukemic cells. Anti-HA magnetic beads were used for affinity purification of ETV6-HA (and ETV6 control) from the nuclear and cytoplasmic fraction. Following purification on-beads digest and LC-MS/MS experiments were performed at the Proteomics platform of the CHU de Quebec Research Center, Quebec, Canada.
2022-01-26 | PXD031001 | Pride
Project description:Purpose: FBXW7 is one of the most frequently mutated tumor suppressors, the deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatic analyses and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multi-drug resistance (MDR), to a bigger extent than well-established MDR-drivers such as ABCB1. Proteomic data from FBXW7-deficient cells and human cancer samples identify the upregulation of mitochondrial function as a hallmark of FBXW7 deficiency, which has been previously linked to an increased resistance to chemotherapy. Accordingly, genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. For instance, targeting mitochondrial translation with the antibiotic Tigecycline efficiently kills FBXW7-deficient cells in vitro and in vivo, by a mechanism that involves activation of the Integrated Stress Response (ISR). Searching for additional drugs that overcome MDR in FBXW7-deficient cells, we found several targeted therapies such as Erlotinib, Dasatinib or Vemurafenib which unexpectedly also activate the ISR. Together, our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance. Methods: This study was performed in 2 groups of DLD1 cells with duplicate samples per group. Both control (Wild Type, WT) and experimental (FBXW7 -/-, KO) were exposed to Tigecycline (10µM). DMSO was used as a control for the treatment. After 24h, the RNA was extracted and the transcriptome was profiled with RNA-Sequencing (RNA-seq) analysis. Results: our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance.
2022-06-09 | GSE189499 | GEO
Project description:We assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. This experiment assesses the role of the FBXW7-KMT2D axis in regulating gene expression in OPM-1 cells.
2020-04-07 | GSE148131 | GEO
Project description:Exparession profiling of ETV6-NCOA2 at different stages of disease dEmpty vectorelopment: CD34 cord blood cells transduced with ETV6-NCOA2-GFP or with empty vector-GFP, CD34 cord blood cells transduced with ETV6-NCOA2-NGFR or ETV6-NCOA2-NGFR + NOTCH1-L1601PdP-GFP and transplanted in NSGS mice, and ETV6-NCOA2 patient derived xenografts.
2022-05-16 | GSE161702 | GEO
Project description:Fbxw7 is a tumor supressor frequently mutated in endometrial cancer. To analyze the signaling pathways that can be altered by Fbxw7 we compared RNA expression in the presence or absence of Fbxw7 in mouse endometrial cancer cells deficient for Fbxw7 and Pten.
2019-11-11 | GSE138490 | GEO
Project description:FBXW7 loss-of-function has been implicated in chemoresistance against antimicrotubule drugs. FBXW7 is frequently mutated in human cancers and the identification of FBXW7 substrates, which could be involved in this phenotype, is a major task.
2022-12-02 | PXD035501 | Pride
Project description:We used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that tumors from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments. p53+/â and p53+/âFbxw7+/â mice were generated by crossing p53-/- mice with Fbxw7+/- mice. At 5 weeks of age, mice were exposed whole-body to a single dose of 4 Gy X-ray irradiation. Mice were divided randomly into two groups and treated with rapamycin or placebo. RNA was isolated from thymic lymphomas.
2015-10-31 | E-GEOD-71975 | biostudies-arrayexpress
Project description:FBXW7 is one of the most frequently mutated tumor suppressors, the deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatic analyses and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multi-drug resistance (MDR), to a bigger extent than well-established MDR-drivers such as ABCB1. Proteomic data from FBXW7-deficient cells and human cancer samples identify the upregulation of mitochondrial function as a hallmark of FBXW7 deficiency, which has been previously linked to an increased resistance to chemotherapy. Accordingly, genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. For instance, targeting mitochondrial translation with the antibiotic Tigecycline efficiently kills FBXW7-deficient cells in vitro and in vivo, by a mechanism that involves activation of the Integrated Stress Response (ISR). Searching for additional drugs that overcome MDR in FBXW7-deficient cells, we found several targeted therapies such as Erlotinib, Dasatinib or Vemurafenib which unexpectedly also activate the ISR. Together, our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance.
2022-06-08 | PXD029981 | Pride