UBR1 promotes anaplastic thyroid carcinoma progression via stabilizing YAP through monoubiquitylation
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ABSTRACT:
SUBMITTER: Xia M
PROVIDER: S-EPMC11341911 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Anaplastic thyroid cancer (ATC) is one of the most lethal and aggressive human malignancies, with no effective treatment currently available. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. TAZ is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal TAZ expression in ATC remains to be characterized. In the present study, we identified USP26, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of TAZ in ATC. USP26 was shown to interact with, deubiquitylate, and stabilize TAZ in a deubiquitylation activity-dependent manner. USP26 depletion significantly decreased ATC cell proliferation, migration, and invasion. The effects induced by USP26 depletion could be rescued by further TAZ overexpression. Depletion of USP26 decreased the TAZ protein level and the expression of TAZ/TEAD target genes in ATC, including CTGF, ANKRD1, and CYR61. In general, our findings establish a previously undocumented catalytic role for USP26 as a deubiquitinating enzyme of TAZ and provides a possible target for the therapy of ATC.
| S-EPMC8994751 | biostudies-literature
Project description:BackgroundBladder cancer is one of the most commonly diagnosed urological malignant tumor. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in bladder cancer remains to be characterized.MethodsWestern blot was used to measure the expression of MINDY1 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect the cell viability. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between MINDY1 and YAP. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP.ResultsIn the present study, we identified MINDY1, a DUB enzyme in the motif interacting with ubiquitin-containing novel DUB family, as a bona fide deubiquitylase of YAP in bladder cancer. MINDY1 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. MINDY1 depletion significantly decreased bladder cancer cell proliferation. The effects induced by MINDY1 depletion could be rescued by further YAP overexpression. Depletion of MINDY1 decreased the YAP protein level and the expression of YAP/TEAD target genes in bladder cancer, including CTGF, ANKRD1 and CYR61.ConclusionIn general, our findings establish a previously undocumented catalytic role for MINDY1 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of bladder cancer.
| S-EPMC8314533 | biostudies-literature
Project description:Chromosome instability (CIN) is a common contributor driving the formation and progression of anaplastic thyroid cancer (ATC), but its mechanism remains unclear. The BUB1 mitotic checkpoint serine/threonine kinase (BUB1) is responsible for the alignment of mitotic chromosomes, which has not been thoroughly studied in ATC. Our research demonstrated that BUB1 was remarkably upregulated and closely related to worse progression-free survival. Knockdown of BUB1 attenuated cell viability, invasion, migration and induced cell cycle arrests, whereas overexpression of BUB1 promoted the cell cycle progression of papillary thyroid cancer cells. BUB1 knockdown remarkably repressed tumour growth and tumour formation of nude mice with ATC xenografts and suppressed tumour metastasis in a zebrafish xenograft model. Inhibition of BUB1 by its inhibitor BAY-1816032 also exhibited considerable anti-tumour activity. Further studies showed that enforced expression of BUB1 evoked CIN in ATC cells. BUB1 induced CIN through phosphorylation of KIF14 at serine1292 (Ser1292 ). Overexpression of the KIF14ΔSer1292 mutant was unable to facilitate the aggressiveness of ATC cells when compared with that of the wild type. Collectively, these findings demonstrate that the BUB1/KIF14 complex drives the aggressiveness of ATC by inducing CIN.
| S-EPMC10948175 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) ranks as the second leading cause of global cancer-related deaths and is characterized by a poor prognosis. Eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) have been proved to play important roles in various human cancers, whereas the deubiquitination of EEF1A1 was poorly understood.MethodsThe binding and regulatory relationship between Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) and EEF1A1 was validated using clinical tissue samples, reverse transcription quantitative real-time fluorescence quantitative PCR (RT-qPCR), Western blotting, co-immunoprecipitation, and immunofluorescence, as well as ubiquitin detection and cyclohexamide tracking experiments. Finally, the impact of the UCHL3/EEF1A1 axis on HCC malignant behavior was analyzed through functional experiments and nude mouse models.ResultsUCHL3 was found to have a high expression level in HCC tissues. Tissue samples from 60 HCC patients were used to evaluate the correlation between UCHL3 and EEF1A1. UCHL3 binds to EEF1A1 through the lysine site, which reduces the ubiquitination level of EEF1A1. Functional experiments and nude mouse models have demonstrated that the UCHL3/EEF1A1 axis promotes the migration, stemness, and drug resistance of HCC cells. Reducing the expression of EEF1A1 can reverse the effect of UCHL3 on the malignant behavior of HCC cells.ConclusionOur findings revealed that UCHL3 binds and stabilizes EEF1A1 through deubiquitination. UCHL3 and EEF1A1 formed a functional axis in facilitating the malignant progression of HCC, proving new insights for the anti-tumor targeted therapy for HCC.
| S-EPMC11225194 | biostudies-literature
Project description:Esophageal squamous carcinoma (ESCC) is the major subtype of esophageal cancer in China, accounting for 90% of cases. Recent studies revealed that abnormalities in the Hippo/YAP axis are pervasive in ESCC and are recognized as the important driver of ESCC progression. Since the activity of Hippo signaling is controlled by phosphorylation cascade, it is a mystery why the major effector YAP is still over-activated when the cascade is inhibited. Several studies suggested that in addition to phosphorylation, other protein modifications such as ubiquitination also play important roles in manipulating Hippo/YAP signaling activity. Since YAP protein stability is controlled via an appropriate balance between E3 ubiquitin ligases and deubiquitinases, we performed deubiquitinase siRNA screening and identified USP36 as a deubiquitinase significantly related to Hippo/YAP signaling activity and ESCC progression. USP36 expression was elevated in ESCC samples and correlated with poor differentiation. USP36 expression was correlated with YAP protein levels in ESCC samples. Molecular studies demonstrated that USP36 associated with the YAP protein and enhanced YAP protein stability by blocking the K48-linked polyubiquitination of YAP. In conclusion, our study revealed a novel deubiquitinase in regulating Hippo signaling in ESCC, which could be an encouraging drug target for Hippo-driven ESCC.
| S-EPMC9722938 | biostudies-literature
Project description:Long intergenic noncoding ribonucleic acid (lncRNA) 460 is reportedly associated with carcinogenesis and progression in various types of cancer. However, the mechanisms underlying its action in cutaneous squamous cell carcinoma (CSCC) remain unclear. LINC00460 mRNA expression was analysed using data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cell growth, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), transwell migration and invasion assays after inducing LINC00460 knockdown. A xenograft tumour model was used to determine the effects of LINC00460 on tumour growth and metastasis in vivo. To examine the interaction between LINC00460 and ELAVL1, RNA pulldown and RNA immunoprecipitation assays were performed. LINC00460 was found to be significantly upregulated in CSCC tissues and cell lines. Functionally, LINC00460 knockdown inhibited cell proliferation, migration, and invasion in vitro. Consistent with this, when LINC00460 expression decreased, CSCC tumorigenesis and metastasis in vivo were inhibited. Mechanistically, LINC00460 binds to embryonic lethal abnormal vision like RNA binding protein 1 (ELAVL1) and enhances its stability by inhibiting the β-transducin repeats-containing protein (β-TrCP)-mediated ubiquitination of ELAVL1. Moreover, the effect of LINC00460 silencing on the proliferation, migration, and invasion of CSCC cells could be reversed by overexpressing ELAVL1. Our findings demonstrated that LINC00460 plays a critical role in regulating ELAVL1 function. This highlights the potential targets for the clinical diagnosis and treatment of CSCC.
| S-EPMC10352421 | biostudies-literature
Project description:BackgroundAnaplastic thyroid carcinoma (ATC) is considered to be one of the most aggressive cancers. Our previous study proved that highly expressed lysine acetyltransferase 5 (KAT5) in ATC is associated with a poorer prognosis. Here, this study examined the effects of a KAT5 inhibitor (NU9056) in human ATC cells.MethodsFirst, the Cancer Genome Atlas (TCGA) dataset was used to detect the relationship between KAT5 expression and outcomes of thyroid carcinoma patients. Then, both in vitro and in vivo experiments were conducted to investigate the effects of NU9056 on normal and ATC human thyroid cells. Finally, microRNA sequencing, qPCR, and dual-luciferase reporter assay were performed to explore potential mechanisms by identifying downstream microRNA related to NU9056.ResultsKAT5 dysregulation correlated with more advanced-stage and poorer outcomes of thyroid carcinoma patients. Endogenous KAT5 protein and mRNA levels were much higher in ATC cells than in normal thyroid cells. Suppression of KAT5 by NU9056 inhibited survival, growth, migration, invasion, and tube formation, and increased radiosensitivity and chemosensitivity in ATC cells but showed no impact on normal thyroid cells. Mechanistically, microRNA-202-5p (miR-202) was identified as the most significantly decreased miRNA after NU9056 treatment. Knockdown of miR-202 suppressed ATC cell progression, while forced expression of miR-202 partially blocked the inhibitory effect of NU9056 on ATC cells. Furthermore, c-Myc was validated as the transcription factor of miR-202, and NU9056 decreased the c-Myc protein level by shortening its half-life. Finally, we proved that NU9056 inhibited ATC proliferation in vivo.ConclusionsOur results indicated that NU9056 targets KAT5, shortens c-Myc half-life, subsequently downregulates miR-202 expression, and results in the suppression of ATC cells. Overall, KAT5 could be a potential target for clinical treatment for ATC.
| S-EPMC10279498 | biostudies-literature
Project description:Anaplastic thyroid cancer (ATC) is one of the most aggressive and virulent solid tumors. The ubiquitin proteasome system presents in all eukaryotic cells and is essential for cellular homeostasis. While its underlying role in ATC remains largely unclear. TRIM11 is an E3 ubiquitin ligase and has been reported to act as an oncogene in several human cancers. The present study aims to reveal the oncogenic function of TRIM11 in ATC. Western blot was used to measure the protein expression of TRIM11 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; wound-healing assay and transwell assay were used to measure the migration ability of ATC. The xeno-graft tumor model was used for in vivo study. Immuno-precipitation assay was used to detect the interaction domain between YAP and TRIM11. And the ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. TRIM11 depletion significantly decreases cell proliferation and migration capabilities of ATC cells, and elevates cell sensitivity to chemotherapy, which effect could be further rescued by YAP overexpression. TRIM11 depletion decreases YAP protein level and YAP/TEAD target genes, such as CTGF, ANKRD1 and CYR61 in ATC. Indicating that TRIM11 is a regulator of Hippo signaling pathway. Immuno-precipitation assay shows that the RING domain of TRIM11 is essential for the interaction with WW domain of YAP. Further mechanistic analysis suggests that TRIM11 promotes the mono-ubiquitination of YAP, thus prolongs its protein half. Furthermore, TRIM11 promoter analysis revealed that SOX13 activates TRIM11 transcription by binding to the promoter of TRIM11. In summary, our study describes the oncogenic function of TRIM11 in ATC, which acts as a post-translational modulating factor of Hippo pathway. Targeting TRIM11 may be a potential therapeutic method for ATC treatment.
| S-EPMC7893578 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) have been shown to have several functional roles in tumor biology, and they are deregulated in many types of cancer. The role of a novel lncRNA, NORAD, in papillary thyroid carcinoma (PTC) is still unknown. In this study, we demonstrated that NORAD expression was upregulated in PTC cell lines and samples. Ectopic expression of NORAD promoted PTC cell growth, invasion and migration. Overexpression of NORAD promotes epithelial-to-mesenchymal transition (EMT) progression in the PTC cell. Furthermore, overexpression of NORAD suppressed miR-202-5p expression in PTC cells. The data suggested that miR-202-5p expression was downregulated in PTC cell lines and samples and was negatively correlated with NORAD expression in PTC tissues. Overexpression of miR-202-5p suppressed PTC cell growth, invasion and migration. In addition, we demonstrated that elevated expression of NORAD promoted PTC cell growth, invasion and migration by inhibiting miR-202-5p expression. These results suggested that the lncRNA NORAD acts as an oncogene in PTC progression, partly by regulating miR-202-5p expression.
| S-EPMC6357332 | biostudies-literature
Project description:Emerging evidence have demonstrated that F-box only protein 2 (FBXO2) is intimately associated with malignant tumor development and occurrence. However, neither the functions nor the molecular mechanisms underlying FBXO2 have been determined in the papillary thyroid carcinoma (PTC). The quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry were carried out to detect the FBXO2 expression in PTC tissues. CCK-8 assay, EdU assay and flow cytometry were used to assess cell proliferation, cell cycle and apoptosis. The trans-well assay was conducted to determine the cell invasiveness. The effect of FBXO2 on PTC cell proliferation in vivo was observed through a subcutaneous tumor formation experiment in nude mice. Immunoprecipitation were conducted to detect the interaction between FBXO2 and p53. The ubiquitination assays were conducted to assess the regulation of p53 ubiquitination by FBXO2. FBXO2 was overexpressed in both PTC tissues and cell lines. FBXO2 expression positively correlated with PTC tumor size, lymphatic metastasis, and extramembranous invasion. Furthermore, silencing FBXO2 inhibited PTC cell proliferation and promoted apoptosis. The overexpression of FBXO2 significantly promotes PTC cell proliferation. Mechanistic studies revealed that FBXO2 could directly bind to p53 and promote its ubiquitination degradation. Knockdown of p53 partially reversed the progression arrest induced by FBXO2 Knockdown in PTC cells. FBXO2 knockdown inhibited PTC cell proliferation and promoted apoptosis by targeting p53 for ubiquitination and degradation. This process represents a research foundation for its diagnostic and therapeutic applications.
| S-EPMC11439943 | biostudies-literature