Tripartite motif 8 promotes hepatocellular carcinogenesis by mediating ubiquitination and degradation of hepatocyte nuclear factor 1α
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236348 | GEO | 2023/07/08
REPOSITORIES: GEO
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Project description:Tripartite motif 8 promotes hepatocellular carcinogenesis by mediating ubiquitination and degradation of hepatocyte nuclear factor 1α
| PRJNA990674 | ENA
Project description:Hepatocytes are epithelial cells with highly specialized polarity. The disorder and loss of hepatocyte polarity leads to a weakness of cell adhesion and connection, the induction of epithelial-mesenchymal transition, and eventually the occurrence of hepatocellular carcinoma (HCC). Cluster of differentiation 147 (CD147), a tumor-related glycoprotein, promotes epithelial-mesenchymal transition and the invasion of HCC. However, the function of CD147 in hepatocyte depolarization is unknown. Here we identified that CD147 was basolaterally polarized in hepatocyte membrane of liver tissues and HepG2 cells. CD147 not only promoted transforming growth factor-?1-mediated hepatocyte polarity loss but also directly induced endocytosis and down-regulation of E-cadherin which contributed to hepatocyte depolarization. Overexpression of CD147 induced Src activation and subsequently recruited ubiquitin ligase Hakai for E-cadherin ubiquitination and lysosomal degradation, leading to decreases of partitioning defective 3 expression and ?-catenin nuclear translocation. This signal transduction was initiated by competitive binding of CD147 with integrin ?1 that interrupted the interaction between the Arg-Gly-Asp motif of fibronectin and integrin ?1. The specific antibodies targeting integrin ?5 and ?1 reversed the decrease of E-cadherin and partitioning defective 3 levels induced by CD147 overexpression. In human liver tissues, CD147 polarity rates significantly declined from liver cirrhosis (71.4%) to HCC (10.4%). CD147-polarized localization negatively correlated with Child-Pugh scores in human liver cirrhosis (r = -0.6092, P < 0.0001) and positively correlated with differentiation grades in HCC (r = 0.2060, P = 0.004). HCC patients with CD147-polarized localization had significantly better overall survival than patients with CD147 nonpolarity (P = 0.021). CONCLUSION:The ectopic CD147-polarized distribution on basolateral membrane promotes hepatocyte depolarization by activation of the CD147-integrin ?5?1-E-cadherin ubiquitination-partitioning defective 3 decrease and ?-catenin translocation signaling cascade, replenishing a molecular pathway in hepatic carcinogenesis. (Hepatology 2018;68:317-332).
| S-EPMC6055794 | biostudies-literature
Project description:Glioblastoma (GBM) is the most common malignant primary brain tumor. Despite comprehensive treatment with traditional surgery, radiotherapy, and chemotherapy, the median survival rate is <14.6% and the 5-year survival rate is only 5%. FBXO22, a substrate receptor of the SCF ubiquitin ligases, has been reported to play a promoting role in melanoma, liver cancer, cervical cancer, and other cancers. However, the function of FBXO22 in GBM has not been reported. In the present study, we demonstrate that FBXO22 is highly expressed in glioma and is positively correlated with worse pathological features and shorter survival of GBM patients. We revealed that FBXO22 promotes GBM cell proliferation, angiogenesis, migration, and tumorigenesis in vitro and in vivo. In terms of mechanism, we reveal that FBXO22 decreases VHL expression by directly mediating VHL ubiquitination degradation, which ultimately increases HIF-1α and VEGFA expression. In addition, our data confirm that there are positive correlations among FBXO22, HIF-1α, and VEGFA expression, and there is a negative correlation between FBXO22 and VHL protein expression in glioma patients. Our study strongly indicates that FBXO22 is a promising diagnostic marker and therapeutic target for glioma patients.
| S-EPMC10959977 | biostudies-literature
Project description:IntroductionTRIpartite motif (TRIM) proteins are important members of the Really Interesting New Gene-finger-containing E3 ubiquitin-conjugating enzyme and are involved in the progression of hepatocellular carcinoma (HCC). However, the diverse expression patterns of TRIMs and their roles in prognosis and immune infiltrates in HCC have yet to be analyzed.MaterialsCombined with previous research, we used an Oncomine database and the Human Protein Atlas to compare TRIM family genes' transcriptional levels between tumor samples and normal liver tissues, as verified by the Gene Expression Profiling Interactive Analysis database. We investigated the patient survival data of TRIMs from the Kaplan-Meier plotter database. Clinicopathologic characteristics associations and potential diagnostic and prognostic values were validated with clinical and expressional data collected from the cancer genome atlas.ResultsWe identified TRIM28, TRIM37, TRIM45, and TRIM59 as high-priority members of the TRIMs family that modulates HCC. Low expression of TRIM28 was associated with shorter overall survival (OS) than high expression (log-rank p = 0.009). The same trend was identified for TRIM37 (p = 0.001), TRIM45 (p = 0.013), and TRIM59 (p = 0.011). Multivariate analysis indicated that the level of TRIM37 was a significant independent prognostic factor for both OS (p = 0.043) and progression-free interval (p = 0.044). We performed expression and mutation analysis and functional pathways and tumor immune infiltration analysis of the changes in TRIM factors.ConclusionThese data suggested that TRIM28, TRIM37, TRIM45, and TRIM59 could serve as efficient prognostic biomarkers and therapeutic targets in HCC.
| S-EPMC8986146 | biostudies-literature
Project description:Mutations in E3 ubiquitin ligase Parkin have been linked to familial Parkinson's disease. Accumulating evidence suggests that Parkin is a tumor suppressor, but the underlying mechanism is poorly understood. Here we show that Parkin is an E3 ubiquitin ligase for hypoxia-inducible factor 1α (HIF-1α). Parkin interacts with HIF-1α and promotes HIF-1α degradation through ubiquitination, which in turn inhibits metastasis of breast cancer cells. Parkin downregulation in breast cancer cells promotes metastasis, which can be inhibited by targeting HIF-1α with RNA interference or the small-molecule inhibitor YC-1. We further identify lysine 477 (K477) of HIF-1α as a major ubiquitination site for Parkin. K477R HIF-1α mutation and specific cancer-associated Parkin mutations largely abolish the functions of Parkin to ubiquitinate HIF-1α and inhibit cancer metastasis. Importantly, Parkin expression is inversely correlated with HIF-1α expression and metastasis in breast cancer. Our results reveal an important mechanism for Parkin in tumor suppression and HIF-1α regulation.
| S-EPMC5703960 | biostudies-literature
Project description:Avian influenza A H7N9 emerged in 2013, threatening public health and causing acute respiratory distress syndrome, and even death, in the human population. However, the underlying mechanism by which H7N9 virus causes human infection remains elusive. Herein, we infected A549 cells with H7N9 virus for different times and assessed tripartite motif-containing protein 46 (TRIM46) expression. To determine the role of TRIM46 in H7N9 infection, we applied lentivirus-based TRIM46 short hairpin RNA sequences and overexpression plasmids to explore virus replication, and changes in type I interferons and interferon regulatory factor 3 (IRF3) phosphorylation levels in response to silencing and overexpression of TRIM46. Finally, we used Co-immunoprecipitation and ubiquitination assays to examine the mechanism by which TRIM46 mediated the activity of TANK-binding kinase 1 (TBK1). Type I interferons play an important role in defending virus infection. Here, we found that TRIM46 levels were significantly increased during H7N9 virus infection. Furthermore, TRIM46 knockdown inhibited H7N9 virus replication compared to that in the control group, while the production of type I interferons increased. Meanwhile, overexpression of TRIM46 promoted H7N9 virus replication and decrease the production of type I interferons. In addition, the level of phosphorylated IRF3, an important interferon regulatory factor, was increased in TRIM46-silenced cells, but decreased in TRIM46 overexpressing cells. Mechanistically, we observed that TRIM46 could interact with TBK1 to induce its K48-linked ubiquitination, which promoted H7N9 virus infection. Our results suggest that TRIM46 negatively regulates the human innate immune response against H7N9 virus infection.
| S-EPMC9632593 | biostudies-literature
Project description:While defective α-synuclein homeostasis is central to Parkinson's pathogenesis, fundamental questions about its degradation remain unresolved. We have developed a bimolecular fluorescence complementation assay in living cells to monitor de novo ubiquitination of α-synuclein and identified lysine residues 45, 58, and 60 as critical ubiquitination sites for its degradation. This is mediated by NBR1 binding and entry into endosomes in a process that involves ESCRT I-III for subsequent lysosomal degradation. Autophagy or the autophagic chaperone Hsc70 is dispensable for this pathway. Antibodies against diglycine-modified α-synuclein peptides confirmed that endogenous α-synuclein is similarly ubiquitinated in the brain and targeted to lysosomes in primary and iPSC-derived neurons. Ubiquitinated α-synuclein was detected in Lewy bodies and cellular models of aggregation, suggesting that it may be entrapped with endo/lysosomes in inclusions. Our data elucidate the intracellular trafficking of de novo ubiquitinated α-synuclein and provide tools for investigating the rapidly turned-over fraction of this disease-causing protein.
| S-EPMC10266730 | biostudies-literature
Project description:Melanoma is one of the most lethal forms of skin cancer because of its early metastatic spread. The variant form of CD44 (CD44v), a cell surface glycoprotein, is highly expressed on metastatic melanoma. The mechanisms of regulation of CD44 alternative splicing in melanoma and its pathogenic contributions are so far poorly understood. Here, we investigated the expression level of CD44 in a large set of melanocytic lesions at different stages. We found that the expression of CD44v8-10 and a splicing factor, U2AF2, is significantly increased during melanoma progression, whereas CD82/KAI1, a tetraspanin family of tumor suppressor, is reduced in metastatic melanoma. CD44v8-10 and U2AF2 expression levels, which are negatively correlated with CD82 levels, are markedly elevated in primary melanoma compared with dysplastic nevi and further increased in metastatic melanoma. We also showed that patients with higher CD44v8-10 and U2AF2 expression levels tended to have shorter survival. By using both in vivo and in vitro assays, we demonstrated that CD82 inhibits the production of CD44v8-10 on melanoma. Mechanistically, U2AF2 is a downstream target of CD82 and in malignant melanoma facilitates CD44v8-10 alternative splicing. U2AF2-mediated CD44 isoform switch is required for melanoma migration in vitro and lung and liver metastasis in vivo. Notably, overexpression of CD82 suppresses U2AF2 activity by inducing U2AF2 ubiquitination. In addition, our data suggested that enhancement of melanoma migration by U2AF2-dependent CD44v8-10 splicing is mediated by Src/focal adhesion kinase/RhoA activation and formation of stress fibers, as well as CD44-E-selectin binding reinforcement. These findings uncovered a hitherto unappreciated function of CD82 in severing the linkage between U2AF2-mediated CD44 alternative splicing and cancer aggressiveness, with potential prognostic and therapeutic implications in melanoma.
| S-EPMC5033661 | biostudies-literature
Project description:Autophagy is a cellular degradative process that has multiple important actions in cancer. Autophagy modulation is under consideration as a promising new approach to cancer therapy. However, complete autophagy dysregulation is likely to have substantial undesirable side effects. Thus, more targeted approaches to autophagy modulation may prove clinically beneficial. One potential avenue to achieving this goal is to focus on the actions of tripartite motif-containing protein family members (TRIMs). TRIMs have key roles in an array of cellular processes, and their dysregulation has been extensively linked to cancer risk and prognosis. As detailed here, emerging data shows that TRIMs can play important yet context-dependent roles in controlling autophagy and in the selective targeting of autophagic substrates. This review covers how the autophagy-related actions of TRIM proteins contribute to cancer and the possibility of targeting TRIM-directed autophagy in cancer therapy.
| S-EPMC7081753 | biostudies-literature
Project description:The role of tripartite motif (TRIM) 38, a ubiquitin E3 ligase regulating various pathophysiological processes, in cardiac fibrosis remains unclear. Here, a model of angiotensin II and myocardial infarction (MI)-induced fibrosis was established to explore its role in cardiac fibrosis and its underlying mechanisms. Cardiac fibrosis in the mouse MI model was mitigated by TRIM38 overexpression, but aggravated by its depletion. Consistently, in vitro overexpression or knockdown of TRIM38 ameliorated or aggravated the proliferation and secretion of cardiac fibroblasts (CFs) exposed to fibrotic stimulation, respectively. Mechanistically, TRIM38 suppressed cardiac fibrosis progression by attenuating TAK1/MAPK signaling. Inhibiting TAK1/MAPK signaling with a pharmacological inhibitor greatly reversed the effects of TRIM38 knockdown on CF secretion. Specifically, TRIM38 interacted with and "targeted" TAB2 and TAB3 for degradation, subsequently inhibiting TAK1 phosphorylation and negatively regulating MAPK signaling. These findings can help develop therapeutic strategies to treat and prevent cardiac fibrosis.
| S-EPMC9379576 | biostudies-literature