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Title:
Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1 | Cell Death & Differentiation
Description:
TRAF-binding domain (Trabid), one of deubiquitination enzymes, was recently reported to activate Wnt/ β-catenin signaling pathway. However, the role of Trabid in tumors including hepatocellular carcinoma (HCC) and the underlying mechanisms controlling its activity remain poorly understood. Here, we report that Trabid is significantly downregulated in HCC tumor samples and cell lines compared with normal controls and that its expression level is negatively correlated with HCC pathological grading, recurrence, and metastasis. The reintroduction of Trabid expression in tumor cells significantly decreases HCC progression as well as pulmonary metastasis. The effect of Trabid on HCC development occurs at least partially through regulation of Twist1 activity. Mechanistically, Trabid forms a complex with Twist1 and specifically cleaves RNF8-induced K63-linked poly-ubiquitin chains from Twist1, which enhances the association of Twist1 with β-TrCP1 and allows for subsequent K48-linked ubiquitination of Twist1. Knockdown of Trabid increases K63-linked ubiquitination, but abrogates K48-linked ubiquitination and degradation of Twist1, thus enhancing HCC growth and metastasis. Interestingly, Twist1 negatively regulates the promoter activity of Trabid, indicating that a double-negative feedback loop exists. Our findings also identify an essential role for activation of Trabid by AKT-mediated phosphorylation at Ser78/Thr117 in negatively regulating Twist1 signaling, which further provides insights into the mechanisms by which Trabid regulates Twist1 ubiquitination. Our results reveal that Trabid is a previously unrecognized inhibitor of HCC progression and metastasis, which sheds light on new strategies for HCC treatment.
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trabid, twist, hcc, cells, fig, expression, akt, article, ubiquitination, cell, metastasis, patients, activity, google, scholar, phosphorylation, levels, significantly, klinked, cancer, study, tissues, analysis, data, rnf, growth, tumor, cas, nature, βtrcp, knockdown, university, protein, overexpression, emt, china, role, shown, supplementary, survival, increased, assay, hekt, medical, inhibits, compared, results, proliferation, antibody, lung,
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nature portfolio privacy policy nature advertising activate wnt/β-catenin pathway wnt/β-catenin signal pathway social media �preferentially” cleaves k29-linked trabid-s78a/t117a mutant failed drosophila immune-deficiency pathway reprints β-trcp1-mediated twist1 ubiquitination wnt/β-catenin pathway [7] rnf8-mediated k63 ubiquitination wnt/β-catenin signaling [6] abrogates k48-linked ubiquitination subsequent k48-linked ubiquitination enhancing k48-linked ubiquitination wnt/β-catenin activation depict trabid full-length previously published data β-trcp1 induced k63 trabid-s78a/t117a mutant computation-based virtual screen p53-dependent apoptotic pathway tgf-β signaling axes routine post-surgical chemotherapy s78a/t117a mutation akt/pkb-mediated phosphorylation double-negative feedback loop regulating twist1 k63-ubiquitination phospho-ser/thr antibody twist1 k48-linked ubiquitination exact chi-square test factor-binding protein domain k63-k48 ubiquitination transition cell death differ trabid-s78d/t117d mutant anti-flag affinity column tumor-necrosis factor receptor vitro k63-linked deubiquitination atypical ubiquitin chains shrna-resistant expression construct log-rank test assays shrna-resistant trabid plasmid trabid promoter-luciferase reporter pgl3-trabid promoter-reporter permissions shtrabid-induced invasive capabilities targeting trabid/twist1 axis
Questions {❓}
- How to coordinate these opposite views?
- However, it is entirely unknown about how these different regulators of Twist1 are reconciled in HCC?
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headline:Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1
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headline:Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1
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Ubiquitylation
Life Sciences
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Biochemistry
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Stem Cells
Apoptosis
Cell Cycle Analysis
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email:[email protected]
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name:Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
name:Medical Center, Duke University, Durham, USA
name:Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
name:Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, China
name:Department of Pharmacy, Xijing Hospital, Fourth Military University, Xiâ an, China
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name:Longju Medical Research Center, Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical College, Zunyi, China
name:Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, The State University of New Jersey, New Brunswick, USA
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