The E3 ubiquitin ligase MAEA promotes macrophage phagocytosis and inhibits gastrointestinal cancer progression by mediating PARP1 ubiquitination and degradation

International Journal of Biological Sciences, Journal Year: 2025, Volume and Issue: 21(4), P. 1784 - 1800

Published: Feb. 10, 2025

Background: While a role for the E3 ubiquitin ligase MAEA (macrophage erythroblast attacher) has been reported in several cancer types, its importance and mechanistic functions gastrointestinal (GIC) have yet to be established. Methods: The of GIC were explored through vitro vivo experiments, including loss- gain-of-function analyses. Mass spectrometry was used identify proteins that interact with MAEA. mechanisms which influences tumor aggression examined immunoprecipitation Results: patients exhibiting reduced expression found exhibit worse disease-free overall survival outcomes. impair proliferation chemoresistance tumors subcutaneous xenograft model systems. combination PARP1 inhibitor veliparib resulted enhanced oxaliplatin treatment efficacy vivo. From perspective, mediate K48-linked ubiquitination degradation PARP1, addition suppressing M2 polarization macrophages enhancing macrophage phagocytic activity. Conclusions: These data suggest offers value as prognostic biomarker target owing ability degrade augment activity macrophages.

Language: Английский

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HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 6, 2025

Protein acetylation modification plays important roles in various aspects of tumor progression. Ferroptosis driven by lethal lipid peroxidation is closely related to development. Targeting ferroptosis has become a promising strategy. However, the crosstalk between protein and remains unclear. In present study, we found that acyl-CoA synthase long-chain family member 4 (ACSL4) enhances its stability double-edged sword regulation nasopharyngeal carcinoma (NPC). On one hand, ACSL4 could promote malignant progress tumors; on other it enhanced radiosensitivity endowing NPC cells with ferroptosis-sensitive properties vitro vivo. Mechanistically, histone acetyltransferase 1 (HAT1) directly promotes at lysine 383, deacetylase sirtuin 3 (SIRT3) mediates deacetylation ACSL4. Meanwhile, another 2 (HDAC2) through inhibiting transcription SIRT3. Acetylation inhibits F-box 10 (FBXO10)-mediated K48-linked ubiquitination, resulting This study reveals novel regulatory mechanism ferroptosis-related from perspective acetylation, provides method for NPC.

Language: Английский

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Unveiling the Role of Protein Posttranslational Modifications in Glioma Prognosis

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(3)

Published: March 1, 2025

ABSTRACT Background Gliomas represent the most aggressive malignancies of central nervous system, with posttranslational modifications (PTMs) emerging as critical regulators oncogenic processes through dynamic protein functional modulation. Despite their established role in tumor biology, systematic characterization PTM‐mediated molecular mechanisms driving glioma progression remains unexplored. This study aims to uncover glioma, a focus on PTMs. Methods We analyzed PTM pathway classify patients into distinct clusters. Comprehensive analyses compared intercluster differences clinical outcomes, mutational landscapes, and immune microenvironment profiles. Differentially expressed genes (DEGs) were identified construct robust prognostic prediction model machine learning approaches. Among included model, TOM1L1 (Target Myb1 Like 1 Membrane Trafficking Protein) was selected for vitro experimental validation assess its progression. Results PTMs found influence prognosis significantly. Dysregulation specific pathways, such glutathionylation citrullination, correlated more features. The comprising DEGs , demonstrated high predictive accuracy (c‐index = 0.867)—the scores derived from strongly indicators. In experiments revealed that facilitates malignant by modulating confirming glioma. Conclusion Our establishes first comprehensive atlas gliomas, revealing subtype‐specific modification patterns therapeutic implications. emerges promising biomarker potential intervention target. Targeting pathways may offer novel strategies treatment, enhancing patient outcomes.

Language: Английский

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Involvement of the ubiquitin-proteasome system in the regulation of the tumor microenvironment and progression

Genes & Diseases, Journal Year: 2024, Volume and Issue: 12(2), P. 101240 - 101240

Published: Feb. 2, 2024

The tumor microenvironment is a complex environment comprising cells, non-tumor and other critical non-cellular components. Some studies about have recently achieved remarkable progress in treatment. As substantial part of post-translational protein modification, ubiquitination crucial player maintaining stability cell signaling, growth, series cellular life activities, which are also essential for regulating cells or the microenvironment. This review focuses on role function deubiquitination modification while discussing prospect developing inhibitors targeting ubiquity-related enzymes, thereby providing ideas future research cancer therapy.

Language: Английский

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CircVPS8 promotes the malignant phenotype and inhibits ferroptosis of glioma stem cells by acting as a scaffold for MKRN1, SOX15 and HNF4A

Oncogene, Journal Year: 2024, Volume and Issue: 43(36), P. 2679 - 2695

Published: Aug. 4, 2024

Language: Английский

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PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(7)

Published: July 23, 2024

Abstract Invasion and migration are the key hallmarks of cancer, aggressive growth is a major factor contributing to treatment failure poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed promote malignant proliferation glioblastoma cells previous studies. However, effects PRMT6 on cell invasion its underlying mechanisms remain elusive. Here, we report that functions driver element for tumor Bioinformatics analysis glioma sample detection results demonstrated highly expressed mesenchymal subtype or invasive gliomas, significantly negatively correlated with their prognosis. Inhibition (using shRNA inhibitor EPZ020411) reduces vitro, whereas overexpression produces opposite effects. Then, identified maintains protein stability EZH2 by inhibiting degradation protein, thereby mediating cells. Further mechanistic investigations found inhibits transcription TRAF6 activating histone methylation mark (H3R2me2a), reducing interaction between enhance Xenograft assay HE staining showed expression could vivo, immunohistochemical mouse brain tissue sections also regulatory relationship PRMT6, TRAF6, EZH2. Our findings illustrate suppresses via H3R2me2a facilitate migration. Blocking PRMT6-TRAF6-EZH2 axis promising strategy

Language: Английский

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PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Invasion and migration are the key hallmarks of cancer, aggressive growth is a major factor contributing to treatment failure poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed promote malignant proliferation GBM cells previous studies. However, effects PRMT6 on cell invasion its underlying mechanisms remain elusive. Here, we report that functions driver element for tumor Bioinformatics analysis glioma sample detection results demonstrated highly expressed mesenchymal subtype or invasive gliomas, significantly negatively correlated with their prognosis. Inhibition (using shRNA inhibitor EPZ020411) reduces in vitro, whereas overexpression produces opposite effects. Then, identified maintains protein stability EZH2 by inhibiting degradation protein, thereby mediating cells. Further mechanistic investigations found inhibits transcription TRAF6 activating histone methylation mark (H3R2me2a), reducing interaction between enhance Xenograft assay HE staining showed expression could vivo, immunohistochemical mouse brain tissue sections also regulatory relationship PRMT6, TRAF6, EZH2. Our findings illustrate suppresses via H3R2me2a facilitate migration. Blocking PRMT6-TRAF6-EZH2 axis promising strategy

Language: Английский

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Nanomaterials exert biological effects by influencing the ubiquitin-proteasome system

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 282, P. 116974 - 116974

Published: Nov. 15, 2024

Language: Английский

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Nodularin‐R Synergistically Enhances Abiraterone Against Castrate‐ Resistant Prostate Cancer via PPP1CA Inhibition

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(22)

Published: Nov. 1, 2024

ABSTRACT Clinically, most prostate cancer (PCa) patients inevitably progress to castration‐resistant (CRPC) with poor prognosis after androgen deprivation therapy (ADT), including abiraterone, the drug of choice for ADT. Therefore, it is necessary explore resistance mechanism abiraterone in depth. Genome‐wide CRISPR/Cas9 knockout technology was used screen CRPC cell line 22Rv1 abiraterone‐resistant genes. Combined bioinformatics, a key gene high expression and screened. Then, effects target on function were explored by silencing overexpression. Further, natural product potential targeting effect identified validated molecular docking protein expression. Molecular dynamics simulations revealed affecting Finally, combined anti‐CRPC cellular vivo experiments. Five common genes (KCNJ3, COL2A1, PPP1CA, MDH2 EXOSC5) successfully, among which PPP1CA had worst disease‐free survival. Moreover, highly expressed cells. Silencing increased sensitivity while promoting apoptosis inhibiting clone formation. Overexpressing exerted opposite effects. binding mode nodularin‐R dose‐dependent manner inhibition. Mechanistically, attenuates interaction between USP11 (deubiquitinating enzyme), potentially degradation. Additionally, combination 2.72 μM 54.5 synergistically inhibited resistant function. In experiments also that significantly tumour growth reduced inducible PPP1CA. driver resistance, enhances

Language: Английский

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PXD101 inhibits malignant progression and radioresistance of glioblastoma by upregulating GADD45A

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 20, 2024

Histone deacetylase inhibitors (HDACis) have shown a significant antitumor effect in clinical studies, and PXD101 is novel HDACi which can cross the blood-brain barrier. In this study, we showed that could significantly inhibit proliferation invasion of glioblastoma (GBM) cells, while promoting their apoptosis radiosensitivity. Furthermore, it was found exerted its function by upregulating expression growth arrest DNA damage inducible protein α (GADD45A). Mechanistically, promoted transcription GADD45A directly acetylating histones H3 H4, enhanced radiosensitivity through activation P38 GBM cells. vivo experiments also combined with radiotherapy GBM. This study provides experimental evidence for application treatment GBM, as well new molecular markers potential intervention targets may be used preventing malignant progression radioresistance.

Language: Английский

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