CELLULAR SIGNALLING
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2025
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IF 3.7
Qingqing Chen,Ling Ouyang
Recent findings have indicated that the F-box E3 ubiquitin ligase, F-box only protein 11 (FBXO11), may serve a tumor-suppressing role in certain types of cancers. However, its specific function in ovarian cancer (OC) remains to be elucidated. This study revealed that FBXO11 expression is reduced in OC tissues compared to normal tissues. To assess the role of FBXO11 in OC cells, we established stable human OC cell lines with tetracycline-inducible (Tet-on) expression of FBXO11 CDS or shRNA. FBXO11 inhibited OC cell proliferation, colony formation, migration, invasion, and cell cycle transition from G0/G1 to S phase in vitro . Moreover, FBXO11 suppressed xenograft tumor growth in mice in vivo . Concurrently, FBXO11 reduced the volume of ascites and the number of metastatic tumor nodules in the peritoneal metastasis model. Mechanistically, FBXO11 promoted kinesin family member 2C (KIF2C) to undergo K48-linked ubiquitination and proteasomal degradation, and KIF2C knockdown reversed the tumor-promoting function of FBXO11 downregulation. Additionally, we demonstrated that FBXO11 is a transcriptional target of zinc-finger protein 217 (ZNF217), a known transcriptional repressor that has been implicated in the promotion of OC progression and the prediction of poor prognosis. In summary, FBXO11 functions as a tumor suppressor in OC through ubiquitin-proteasomal degradation of KIF2C; and the low expression level of FBXO11 in OC may be attributed to its transcriptional inhibition by transcription factor ZNF217. These findings provided new insights into understanding the molecular mechanism of OC progression.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2024
·
IF 8.2
Zuodong Xuan,Chen Chen,Huimin Sun,Kunao Yang,Jinxin Li,Meilin Fu,Yang Bai,Zeyuan Zheng,Yue Zhao,Chunlan Xu,Bin Liu,Tian Li,Chen Shao
Background: Prostate cancer progression hinges on β-catenin's stability and activity, a key factor in epithelial-mesenchymal transition (EMT) and metastasis. This study delves into NDR1-dependent phosphorylation's impact on β-catenin via FBXO11, an E3 ubiquitin ligase, in prostate cancer cells. Methods: Human prostate cancer cell lines underwent various in vitro assays, including real-time PCR, Western blotting, immunoprecipitation, immunofluorescence, and protein stability assays, to explore β-catenin's interactions and post-translational modifications. NDR1 modulation's in vivo efficacy was assessed using a nude mice lung metastasis model. Small-molecule screening identified a potential NDR1 activator, aNDR1, tested for its effects on metastasis via in vitro and in vivo assays. Results: NDR1 phosphorylated β-catenin at Ser33/37, facilitating its interaction with FBXO11. This led to FBXO11-mediated ubiquitination and cytoplasmic degradation of β-catenin, while the NDR1-FBXO11 complex impeded β-catenin nuclear translocation by inducing JNK2 ubiquitination. Thus, NDR1 and FBXO11 jointly regulate β-catenin activity in prostate cancer cells through dual phosphorylation-driven ubiquitination, potentially suppressing EMT. Reduced NDR1 expression inhibited FBXO11 and β-catenin phosphorylation, diminishing β-catenin and JNK2 ubiquitination, promoting EMT and enhancing prostate cancer cell metastasis. The inhibitory effects of aNDR1 on prostate cancer metastasis were validated. Conclusion: The NDR1/FBXO11 axis outlines a non-canonical β-catenin degradation pathway crucial in regulating EMT and prostate cancer cell metastasis. NDR1 activation, particularly with aNDR1, could offer a promising therapeutic avenue against prostate cancer metastasis.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cancers
·
2024
·Vol. 16
·期 19
·3269
·
IF 4.5
Xinyue Zhao,Zhihui Han,Ruiying Liu,Zehao Li,Ling Mei,Yue Jin
Simple SummaryEpithelial-to-mesenchymal transition (EMT) plays a critical role in cancer progression, contributing to the invasive and migratory abilities of tumor cells. In this study, we show that FBXO11 promotes the degradation of ZEB1, a key EMT regulator, via ubiquitination. Loss of FBXO11 increases ZEB1 levels, enhancing the invasiveness of lung cancer cells, while its overexpression reduces ZEB1 and suppresses invasion. Importantly, higher FBXO11 expression is associated with better prognosis in non-small cell lung cancer (NSCLC), highlighting its potential role as a therapeutic target for controlling EMT and cancer metastasis.AbstractEpithelial-to-mesenchymal transition (EMT) affects the invasion and migration of cancer cells. Here, we show that FBXO11 recognizes and promotes ubiquitin-mediated degradation of ZEB1. There is a strong association between FBXO11 and ZEB1 in non-small cell lung cancer (NSLC) in a clinical database. FBXO11 interacts with ZEB1, a core inducer of EMT. FBXO11 leads to increased ubiquitination and proteasomal degradation of ZEB1. Depletion of endogenous FBXO11 causes ZEB1 protein accumulation and EMT in A549 and H1299 cells, while overexpression of FBXO11 reduces ZEB1 protein abundance and cellular invasiveness. Importantly, the depletion of ZEB1 suppresses the increased migration and invasion of A549 and H1299 cells promoted by the depletion of FBXO11. The same results are shown in xenograft tumors. High FBXO11 expression is associated with a favorable prognosis in NSLC. Collectively, our study demonstrates that FBXO11 modulates EMT by mediating the stability of ZEB1 in lung cancer cells.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2024
·
IF 3.3
Yanhua Jin,Huan Wang,Yu Xin,Yanning Zhang
Mitochondrial dysfunction is a pivotal factor in the onset of podocyte damage, which is a central component in the pathogenesis of nephrotic syndrome (NS). However, the precise mechanisms underlying the changes in podocyte mitochondria remain elusive. Our study aims to clarify the potential mechanisms involved in the role of F-box protein 11 (Fbxo11) in NS, specifically concentrating on its impact on mitochondrial function. A mouse model was established by tail vein injection of adriamycin (ADR, 10 mg/kg) and was infected with lentivirus overexpressing Fbxo11. Mouse podocytes (MPC-5) were infected with lenti-Fbxo11-OE, followed by treatment with 0.4 μg/mL of ADR. We identified the decreased expression of Fbxo11 in mouse kidney tissues and MPC-5 cells induced by ADR. Lenti-Fbxo11-OE intervention relieved ADR-induced glomerular lesion, podocyte injury, and mitochondrial dysfunction. In vitro, overexpression of Fbxo11 in mouse podocytes improved mitochondrial function and reduced podocyte damage, thereby inhibiting podocyte apoptosis. Mechanistically, Fbxo11 decreased the protein expression of Fosl2 through ubiquitin-dependent proteasomal degradation. Rescue experiments revealed that overexpression of Fosl2 abolished the protective effects of Fbxo11 overexpression on mitochondrial damage and podocyte injury. Importantly, the regulatory effects of the Fbxo11/Fosl2 axis were reversed when treated with the mitochondrial fission inhibitor mdivi-1. Taken together, our results demonstrated that Fbxo11-mediated ubiquitin degradation of Fosl2 is critical for maintaining mitochondrial function and preventing podocyte injury during NS.
研究领域:
肾病学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
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