FBXW7/GSK3β-mediated degradation of PRR11 inhibits RCC progression via oxidative DNA damage
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ABSTRACT:
PROVIDER: PRJNA1100454 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28681874_1.fastq.gz | Fastqsanger.gz | |||
| SRR28681874_2.fastq.gz | Fastqsanger.gz | |||
| SRR28681875_1.fastq.gz | Fastqsanger.gz | |||
| SRR28681875_2.fastq.gz | Fastqsanger.gz | |||
| SRR28681876_1.fastq.gz | Fastqsanger.gz |
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Project description:In our previous study, we reported that proline-rich 11 (PRR11) expression is upregulated in renal cell carcinoma (RCC) and is involved in the regulation of cell cycle and apoptosis. Here, we continued to investigate the pro-carcinogenic role of PRR11 and found that PRR11 regulates oxidative DNA damage via activation of the AKT pathway, which promotes the proliferation and migration of RCC. Mechanistically, GSK3β recognizes and phosphorylates the CPD motif of PRR11, followed by FBXW7 binding to PRR11 and promoting its K48-linked ubiquitination and degradation via the CPD motif of PRR11. In addition, PRR11 can inhibit GSK3β activity via activation of AKT signaling, which in turn prevents the formation of PRR11-phosphorylated CPDs, thereby preventing FBXW7-mediated ubiquitination and degradation of PRR11. This PRR11-AKT interaction establishes a positive feedback loop that continually strengthens the expression of both and accelerates the progression of RCC. Overall, we reveal the specific mechanism by which FBXW7-GSK3β targets PRR11 degradation in RCC and PRR11 affects RCC proliferation and migration by regulating oxidative DNA damage, providing a new target and interventions for RCC therapy.
2025-03-19 | GSE263951 | GEO
Project description:Insulin resistance, a harbinger of the metabolic syndrome, is a state of compromised hormonal response for which transcriptional dysregulation is a major contributor. Genetic or pharmacological inhibition of the nuclear receptor ERRα preserves insulin sensitivity during diet-induced obesity. However, how ERRα integrates insulin signaling at the molecular level with whole body metabolism remains unknown. Herein, we reveal that insulin-mediated gene expression requires the nuclear stabilization of ERRα through a GSK3β/FBXW7 axis. Liver-specific deletion of GSK3β or FBXW7 or mice harboring mutations of ERRα phosphosites (ERRα3SA) co-targeted by GSK3β/FBXW7 result in accumulated ERRα proteins that no longer respond to insulin. ERRα3SA mice display reprogrammed liver and muscle transcriptomes, resulting in insulin resistance and compromised metabolic homeostasis, effects largely reversed by pharmacological inhibition of ERRα. These findings uncovered a previously unrecognised ERRα-dependent insulin regulatory pathway that could be targeted to improve insulin resistance and associated metabolic diseases.
2022-03-16 | GSE182000 | GEO
Project description:Transcriptional regulation of insulin action and sensitivity via a GSK3β-FBXW7-ERRα axis
| PRJNA754164 | ENA
Project description:Rationale: Renal cell carcinoma (RCC) is a highly malignant and common urological tumor. In our previous study, we reported the upregulation of PRR11 in RCC, emphasizing its important role in cell cycle regulation and apoptosis. In this follow-up study, we aim to further investigate the carcinogenic mechanism of PRR11. Methods: Immunoprecipitation-mass spectrometry (IP-MS), ubiquitination assays, and in vitro phosphorylation assays were used to investigate the phosphorylation and ubiquitination-mediated degradation of PRR11 by FBXW7 and GSK3β. RNA-seq analysis of PRR11 knockdown RCC cells and cellular functional assays, including flow cytometry and comet assays, were performed to explore downstream signaling pathways and regulatory functions. Mouse subcutaneous tumor, tail vein lung metastasis, and popliteal lymph node metastasis models were established to validate PRR11's role in vivo. Results: Our results reveal that GSK3β recognizes and phosphorylates the CDC4 phosphodegron (CPD) consensus motif of PRR11, enabling FBXW7 to bind to PRR11 and catalyze its K48-linked ubiquitination and degradation. Moreover, PRR11 activates AKT signaling, which inhibits GSK3β activity. This inhibition prevents the phosphorylation of CPD motifs on PRR11, thereby obstructing FBXW7-mediated ubiquitination and degradation. The interaction between PRR11 and AKT creates a positive feedback loop that increases the level of both proteins, which ultimately accelerates RCC progression by inhibiting oxidative DNA damage. Conclusion: The FBXW7/GSK3β-PRR11-AKT axis plays a pivotal role in the development of RCC by regulating oxidative DNA damage. Targeting PRR11 may be a potential therapeutic strategy for RCC.
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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: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: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: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