FBXL14 inhibits foam cell formation and atherosclerosis plaque progression by activating the NRF2 signal axis through ubiquitination of DUSP6

Journal of Receptors and Signal Transduction, Год журнала: 2025, Номер unknown, С. 1 - 11

Опубликована: Март 7, 2025

Atherosclerosis is characterized by persistent inflammatory condition, leading to various cardiovascular complications. Foam cell formation, resulting from macrophage uptake of oxidized low-density lipoprotein (ox-LDL), contributes significantly atherosclerosis progression. This study was designed investigate the involvement bispecific phosphatase-6 (DUSP6) and its potential regulatory mechanisms in foam formation atherosclerosis. We employed THP-1 cells induce formation. The lipid droplet accumulation, cholesterol content, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 levels were evaluated using Oil Red O staining, assay, ELISA, qRT-PCR techniques. investigated DUSP6 ubiquitination via immunoprecipitation western blot (WB) analysis. A bioinformatics approach identified FBXL14 as a E3 ligase involved ubiquitination, further confirmed siRNA overexpression experiments. impact on NRF2 signaling pathway assessed WB interference suppressed secretion. Upon ox-LDL treatment, underwent deubiquitylation, with emerging candidate ligase. induced activation. It counteracted inflammation. In ApoE-/- mice, sh-DUSP6 adenovirus injection mitigated atherosclerotic lesion progression improved profile, increased proteins expression NQO1, HO-1, aortic tissue. play vital roles modulating responses Targeting these molecules could offer therapeutic attenuating atherosclerosis-related Not applicable.

Язык: Английский

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USP39/SMC4 promotes hepatoma cell proliferation and 5-FU resistance

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 14, 2025

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by high rate postoperative recurrence and poor long-term survival outcomes. Structural maintenance chromosome 4 (SMC4) frequently overexpressed in various types cancer plays pivotal role tumor cell growth, migration, invasion. Bioinformatics analysis has revealed significant correlation between the tumor-node metastasis (TNM) stage (P < 0.01) SMC4 expression 0.05), was associated with prognosis HCC. Furthermore, identified as an independent prognostic factor for Ubiquitin-specific peptidase 39 (USP39) found whether regulation observed to affect protein synthesis or stability through bioinformatics immunoprecipitation. The levels cellular localization USP39 hepatoma cells were evaluated using quantitative real-time PCR (qPCR), western blotting, immunohistochemistry (IHC), all which indicated significantly elevated roles SMC4/USP39 further investigated several assays, including 3-(4,5-Dimethylthiazol-2-yl) -2,5- diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-2′-deoxyuridine (EdU) incorporation wound healing assay. results demonstrated that USP39/SMC4 crucial enhancing viability proliferation HepG2 cells. Additionally, ZNF207 TIAL1 potential target proteins SMC4. Drug-resistant lines established, both MTT EdU assays performed assess proliferation. HepG2/5-FU regained their sensitivity 5-FU following knockdown either also restored cells, effectively inhibiting Our study underscores HCC development suggests may contribute drug resistance lines, potentially interactions ZNF207.

Язык: Английский

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Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration

Cancer Gene Therapy, Год журнала: 2024, Номер 31(4), С. 599 - 611

Опубликована: Янв. 25, 2024

Abstract Irregularities in insulin signaling have significantly increased the risk of various cancers, yet precise underlying mechanisms remain unclear. Within our study, we observed that inhibiting neddylation enhances cancer cell migration across different types by activating both receptor substrates 1 and 2 (IRS1 IRS2), along with PI3K/AKT pathway. Notably, context high-grade serous carcinoma (HGSC) patients, whether they had type diabetes mellitus or not, IRS1 IRS2 displayed a parallel relationship each other while exhibiting an inverse NEDD8. We also identified C-CBL as E3 ligase responsible for neddylating IRS2, clinical evidence further confirming reciprocal between pAKT, thereby reinforcing tumor suppressive role C-CBL. Altogether, these findings suggest genuinely participates IRS2-dependent signaling, effectively suppressing migration. Thus, caution is advised when considering inhibitors treatment option particularly those presenting dysregulations linked to conditions like obesity-related hyperinsulinemia.

Язык: Английский

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Functional mechanism of hypoxia‐like conditions mediating resistance to ferroptosis in cervical cancer cells by regulating KDM4A SUMOylation and the SLC7A11/GPX4 pathway

Environmental Toxicology, Год журнала: 2024, Номер 39(8), С. 4207 - 4220

Опубликована: Май 10, 2024

The discovery of ferroptosis has unveiled new perspectives for cervical cancer (CC) management. We elucidated the functional mechanism hypoxia-like conditions in CC cell resistance. cells were subjected to normoxia or conditions, followed by erastin treatment induce ferroptosis. assessment viability/ferroptosis resistance was performed MTT assay/Fe

Язык: Английский

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Circ-RAPGEF5 promotes intrahepatic cholangiocarcinoma progression by stabilizing SAE1 to facilitate SUMOylation

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Сен. 13, 2023

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with a poor prognosis. The underlying functions and mechanisms of circular RNA SUMOylation in the development ICC remain poorly understood. Circular hsa_circ_0001681 (termed Circ-RAPGEF5 hereafter) was identified by sequencing from 19 pairs adjacent tissue samples. biological function tumor proliferation metastasis examined series vitro assays. A preclinical model used to validate therapeutic effect targeting Circ-RAPGEF5. pull-down dual-luciferase reporter assays were access interactions. Western blot Co-IP detect levels. Circ-RAPGEF5, which generated exons 2 6 host gene RAPGEF5, upregulated ICC. In vivo showed that promoted metastasis, inhibited apoptosis. Additionally, high expression significantly correlated Further investigation SAE1, potential target also associated oncological outcomes. interaction miR-3185 SAE1. western capable regulating SUMOylation. promotes progression acting as sponge for stabilize Targeting or SAE1 might be novel diagnostic strategy

Язык: Английский

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Ubiquitination, SUMOylation, and NEDDylation related genes serve as prognostic and therapeutic biomarkers for oral squamous cell carcinoma

Journal of Oral Pathology and Medicine, Год журнала: 2024, Номер 53(2), С. 114 - 123

Опубликована: Янв. 17, 2024

Abstract Background Ubiquitination, small ubiquitin‐related modifiers, and NEDDylation are now found to function in cancer biology; however, its role the oral patients remains unclear. Methods A set of bioinformatic tools was integrated analyze expression prognostic significance ubiquitin ubiquitin‐like (UB/UBL) genes. UB/UBL‐related risk score developed via correlation analyses, univariate Cox regression, multivariate regression. Nomogram analysis evaluates model's prediction performance. The drug sensitivity analysis, immune profiles UB/UBL‐classified squamous cell carcinoma (OSCC) patients, their related pathway were investigated, genes therapy analyzed. Results total six obtained. PSMD3, PCGF2, H2BC10 significantly downregulated OSCC tissue associated with longer survival time. high‐risk group showed a lower overall enriched cancer‐related pathways. potential UB/UBL discovered, scores an increase protumor infiltrates high checkpoints. Moreover, area under curve annual rate 0.616, 0.671, 0.673, respectively. Besides, more sensitive docetaxel, doxorubicin, methotrexate therapy. Conclusions We construct prognosis model for try find new approach treating patients. signature is helpful developing tumor markers, prediction, guiding treatment

Язык: Английский

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Role of protein Post-translational modifications in enterovirus infection

Frontiers in Microbiology, Год журнала: 2024, Номер 15

Опубликована: Фев. 26, 2024

Enteroviruses (EVs) are the main cause of a number neurological diseases. Growing evidence has revealed that successful infection with enteroviruses is highly dependent on host machinery, therefore, proteins play pivotal role in viral infections. Both and can undergo post-translational modification (PTM) which regulate protein activity, stability, solubility interactions other proteins; thereby influencing various biological processes, including cell metabolism, metabolic, signaling pathways, death, cancer development. During infection, both life cycle through PTMs different mechanisms, regulation entry, synthesis, genome replication, antiviral immune response. Therefore, important roles EV Here, we review host- virus-associated during enterovirus infection.

Язык: Английский

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Impacts of Nutlin-3a and exercise on murine double minute 2–enriched glioma treatment

Neural Regeneration Research, Год журнала: 2024, Номер 20(4), С. 1135 - 1152

Опубликована: Март 1, 2024

JOURNAL/nrgr/04.03/01300535-202504000-00029/figure1/v/2024-07-06T104127Z/r/image-tiff Recent research has demonstrated the impact of physical activity on prognosis glioma patients, with evidence suggesting exercise may reduce mortality risks and aid neural regeneration. The role small ubiquitin-like modifier (SUMO) protein, especially post-exercise, in cancer progression, is gaining attention, as are potential anti-cancer effects SUMOylation. We used machine learning to create SUMO-related gene signature (ESLRS). This shows how might help improve outlook for low-grade other cancers. prognostic immunotherapeutic significance ESLRS markers, specifically highlighting murine double minute 2 (MDM2), a component ESLRS, can be targeted by nutlin-3. underscores intricate relationship between natural compounds such nutlin-3 immune regulation. Using comprehensive CRISPR screening, we validated specific genes progression. also revealed insights into effectiveness Nutlin-3a potent MDM2 inhibitor through molecular docking dynamic simulation. inhibited cell proliferation activated p53 pathway. Its efficacy decreased overexpression, this was reversed or exercise. Experiments using mouse model highlighted effect oxidative stress pathway Notably, both administration improved function mice bearing tumors derived from MDM2-overexpressing cells. These results suggest Nutlin-3a, an inhibitor, therapeutic approach management. Our supports use products therapy sheds light interaction exercise, products, regulation treatment.

Язык: Английский

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FOXO1-regulated lncRNA CYP1B1-AS1 suppresses breast cancer cell proliferation by inhibiting neddylation

Breast Cancer Research and Treatment, Год журнала: 2023, Номер 202(2), С. 397 - 408

Опубликована: Авг. 28, 2023

Abstract Purpose Overactivated neddylation is considered to be a common event in cancer. Long non-coding RNAs (lncRNAs) can regulate cancer development by mediating post-translational modifications. However, the role of lncRNA modification remains unclear. Methods LncRNA cytochrome P450 family 1 subfamily B member antisense RNA (CYP1B1-AS1) expression breast tissues was evaluated RT-PCR and TCGA BRCA data. Gain loss function experiments were performed explore CYP1B1-AS1 cell proliferation apoptosis vitro vivo. Luciferase assay, CHIP-qPCR transcriptome sequencing, RNA-pulldown mass spectrometry, RIP-PCR Western blot used investigate regulatory factors molecular mechanism involved modification. Results We found that down-regulated correlated with prognosis. In vivo functional confirmed inhibited induced apoptosis. Mechanistically, regulated transcription factor, forkhead box O1 (FOXO1), could upregulated inhibiting PI3K/FOXO1 pathway. Moreover, bound directly NEDD8 activating enzyme E1 subunit (NAE1) protein neddylation. Conclusion This study reports for first time inhibits affect proliferation, which provides new strategy treatment targeting

Язык: Английский

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Regulation of Redox Homeostasis Through DNA/RNA Methylation and Post-Translational Modifications in Cancer Progression

Antioxidants and Redox Signaling, Год журнала: 2023, Номер 39(7-9), С. 531 - 550

Опубликована: Июль 18, 2023

Significance: Aberrant redox homeostasis, characterized by the enhancement of intracellular reactive oxygen species (ROS) and antioxidant defenses, is among well-known cancer hallmarks. Understanding regulatory mechanisms homeostasis in cells has become focus many studies. Epigenetic post-translational modifications (PTMs), as pivotal regulators multiple biological processes, play critical roles tumorigenesis development. Recent Advances: DNA RNA methylation are important forms epigenetic modifications. evidence suggests that DNA/RNA PTMs can modulate manners including affecting key molecules ROS production, elimination, redox-related signaling, thereby participating tumor progression. Critical Issues: The effects on crucial importance for In this review, we introduce dual role cancer, then mechanistic PTMs, especially ubiquitination acetylation, regulating to involve Future Directions: A complete understanding how epigenetics function regulation progression might expand a new direction therapeutic targets cancer. Antioxid. Redox Signal. 39, 531-550.

Язык: Английский

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