TRIM59-mediated ferroptosis enhances neuroblastoma development and chemosensitivity through p53 ubiquitination and degradation
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PROVIDER: S-EPMC10906161 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:Human esophageal cancer (hESC) cell motility adopts various modes, resulting in hESC progression and poor survival. However, how tripartite motif 59 (TRIM59), as the ubiquitination machinery, participates in hESC metastasis is not completely understood. The results indicated that TRIM59 was aberrantly upregulated in hESC tissues compared with adjacent healthy esophageal tissues, which was associated with poor survival and advanced TNM state among patients with hESC. Moreover, patients with hESC with higher TRIM59 expression displayed undetectable p53 expression, which contributed to enhanced progression and motility of hESC. At the molecular level, TRIM59 was indicated to be an E3 putative ubiquitin ligase that targeted the p53 protein, leading to increased degradation of p53, which resulted in decreased chemosensitivity to cisplatin. TRIM59 knockdown reduced TRIM59 expression, increased p53 protein expression, and decreased hESC cell viability, clone formation and migration compared with the small interfering RNA negative control (siNC) group. Furthermore, hESC cell lines were more sensitive to cisplatin in the TRIM59-knockdown group compared with the siNC group. The results indicated a relationship between TRIM59, p53 and the chemosensitivity of cisplatin. The present study suggested that TRIM59 may serve as a promising prognostic indicator for patients with hESC.
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Project description:Bisphosphonates (BPs)-related osteonecrosis of jaw (BRONJ) is a severe complication of the long-term administration of BPs. The development of BRONJ is associated with the cell death of osteoclasts, but the underlying mechanism remains unclear. In the current study, the role of Zoledronic acid (ZA), a kind of bisphosphonates, in suppressing the growth of osteoclasts was investigated and its underlying mechanism was explored. The role of ZA in regulating osteoclasts function was evaluated in the RANKL-induced cell model. Cell viability was assessed by cell counting kit-8 (CCK-8) assay and fluorescein diacetate (FDA)-staining. We confirmed that ZA treatment suppressed cell viability of osteoclasts. Furthermore, ZA treatment led to osteoclasts death by facilitating osteoclasts ferroptosis, as evidenced by increased Fe2+, ROS, and malonyldialdehyde (MDA) level, and decreased glutathione peroxidase 4 (GPX4) and glutathione (GSH) level. Next, the gene expression profiles of alendronate- and risedronate-treated osteoclasts were obtained from Gene Expression Omnibus (GEO) dataset, and 18 differentially expressed genes were identified using venn diagram analysis. Among these 18 genes, the expression of F-box protein 9 (FBXO9) was inhibited by ZA treatment. Knockdown of FBXO9 resulted in osteoclasts ferroptosis. More important, FBXO9 overexpression repressed the effect of ZA on regulating osteoclasts ferroptosis. Mechanistically, FBXO9 interacted with p53 and decreased the protein stability of p53. Collectively, our study showed that ZA induced osteoclast cells ferroptosis by triggering FBXO9-mediated p53 ubiquitination and degradation.
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Project description:The RING finger proteins HdmX and Hdm2 share significant structural and functional similarity. Hdm2 is a member of the RING finger family of ubiquitin-protein ligases E3 and targets the tumor suppressor protein p53 for degradation. Although HdmX also binds to p53, HdmX does not induce p53 degradation. Moreover, HdmX has been reported to interfere with p53 degradation in overexpression experiments. To obtain insight into the mechanism by which HdmX interferes with p53 degradation, we studied the effect of HdmX on the E3 activity of Hdm2 in vitro. Surprisingly, this revealed that HdmX stimulates Hdm2-mediated ubiquitination of p53 and that HdmX facilitates ubiquitination of Hdm2 and vice versa. In addition, down-regulation of HdmX expression within cells results in the accumulation of both p53 and Hdm2. Because HdmX alone does not have appreciable E3 activity, these data indicate that HdmX acts as a stimulator, rather than as an inhibitor, of the E3 activity of Hdm2 and that, at least under certain conditions, HdmX is actively involved in the degradation of both p53 and Hdm2.
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Project description:Backgroundα-Crystallin B (CRYAB) is a chaperone member of the HSPs family that protects proteins with which it interacts from degradation. This study aims to investigate the effect of CRYAB on the progression of colorectal cancer (CRC) and its underlying mechanism.MethodsCRYAB expression was evaluated in CRC tissues. Cell growth was tested by CCK-8 kit. Lipid reactive oxygen species (ROS) assays, lipid peroxidation assays, glutathione assays were used to assess the degree of cellular lipid peroxidation of CRC cells. The potential signal pathways of CRYAB were analyzed and verified by Western blot (WB) and immunoprecipitation (Co-IP).ResultsCRYAB expression was elevated in CRC tissues and exhibited sensitivity and specificity in predicting CRC. Functionally, knockdown of CRYAB induced ferroptosis in CRC cells. Mechanistically, CRYAB binding prevented from β-catenin interacting with TRIM55, leading to an increase in β-catenin protein stability, which desensitized CRC cells to ferroptosis and ultimately accelerated cancer progression.ConclusionsTargeting CRYAB might be a promising strategy to enhance ferroptosis and improve the efficacy of CRC therapy.
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Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease around the world. However, no specific medicine has been approved for NAFLD treatment. Our study was conducted to explore the role and mechanism of TRIM59 in NAFLD, aiming to provide a novel target for NAFLD treatment. Here, the expression of TRIM family members was detected in 10 mild and severe NAFLD tissues as well as 10 normal tissues. TRIM59 expression was verified in 10 normal tissues and 25 mild and severe NAFLD tissues. Palmitic acid and high-fatty diet were used for the construction of NAFLD models. Oil Red O staining was used to detect the level of steatosis. The content of TNF-α, IL-6, and IL-8 was measured to reflect the level of inflammation. Lipid reactive oxygen species was estimated by flow cytometry. We found that TRIM59 was highly expressed in NAFLD tissues compared with normal liver tissues. The inhibition of TRIM59 could inhibit the steatosis and inflammation in NAFLD, whereas its overexpression exhibited reversed effects. The application of ferroptosis inhibitor, deferoxamine, could markedly ameliorate steatosis and inflammation, which was mediated by overexpressed TRIM59. Besides, TRIM59 was demonstrated to interact with GPX4 and promoted its ubiquitination. The overexpression of GPX4 could significantly reverse the pathogenic effects of TRIM59 in NAFLD. Additionally, the inhibition of TRIM59 appeared to be a promising strategy to ameliorate NAFLD in mice model. In summary, our study revealed that TRIM59 could promote steatosis and ferroptosis in NAFLD via enhancing GPX4 ubiquitination. TRIM59 could be a potential target for NAFLD treatment.
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Project description:Tumor suppression by inducing NCOA4-mediated ferroptosis has been shown to be feasible in a variety of tumors, including gliomas. However, the regulatory mechanism of ferroptosis induced by NCOA4 in glioma has not been studied deeply. HECW1 and ZNF350 are involved in the biological processes of many tumors, but their specific effects and mechanisms on glioma are still unclear. In this study, we found that HECW1 decreased the survival rate of glioma cells and enhanced iron accumulation, lipid peroxidation, whereas ZNF350 showed the opposite effect. Mechanistically, HECW1 directly regulated the ubiquitination and degradation of ZNF350, eliminated the transcriptional inhibition of NCOA4 by ZNF350, and ultimately activated NCOA4-mediated iron accumulation, lipid peroxidation, and ferroptosis. We demonstrate that HECW1 induces ferroptosis and highlight the value of HECW1 and ZNF350 in the prognostic evaluation of patients with glioma. We also elucidate the mechanisms underlying the HECW1/ZNF350/NCOA4 axis and its regulation of ferroptosis. Our findings enrich the understanding of ferroptosis and provide potential treatment options for glioma patients.
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