Post-Translational Modifications of Proteins Orchestrate All Hallmarks of Cancer

Life, Journal Year: 2025, Volume and Issue: 15(1), P. 126 - 126

Published: Jan. 18, 2025

Post-translational modifications (PTMs) of proteins dynamically build the buffering and adapting interface between oncogenic mutations environmental stressors, on one hand, cancer cell structure, functioning, behavior. Aberrant PTMs can be considered as enabling characteristics long they orchestrate all malignant variability in proteome cells, cancer-associated tumor microenvironment (TME). On other enhance anticancer mechanisms tumoral ecosystem or sustain beneficial effects oncologic therapies through degradation inactivation carcinogenic or/and activation tumor-suppressor proteins. In this review, we summarized analyzed a wide spectrum involved regulatory that drive tumorigenesis, genetic instability, epigenetic reprogramming, events metastatic cascade, cytoskeleton extracellular matrix (ECM) remodeling, angiogenesis, immune response, tumor-associated microbiome, metabolism rewiring most important hallmarks cancer. All develop due to proteins, which modulate gene transcription, intracellular signaling, protein size, activity, stability localization, trafficking, secretion, half-life, protein–protein interactions (PPIs). associated with exploited better understand underlying molecular heterogeneous chameleonic disease, find new biomarkers progression prognosis, personalize oncotherapies, discover targets for drug development.

Language: Английский

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GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: Jan. 25, 2025

Abstract Background Exosomes, as extracellular membrane vesicles, play important roles in intercellular communication and can influence tumour progression. Circular RNAs (circRNAs) have been reported various malignancies are also components of exosomes. However, the role exosomal circRNAs gastric cancer (GC) progression has not completely clarified. Methods The enriched GC were identified using circRNA sequencing. biological function circMAN1A2 was investigated a series vitro vivo experiments. PKH-67 staining used to label molecular mechanism via mass spectrometry, immunoprecipitation, Western blot, single-cell RNA-sequencing data analyses. Results In our study, we determined that (hsa_circ_0000118) GC-derived Higher expression related poor survival patients (HR = 2.917, p 0.0120). Exosomal promoted suppressed antitumour activity T cells. Moreover, bound SFPQ cells cells, promoting G1/S phase transition cell cycle while inhibiting activation receptor signalling pathway decrease activity. Mechanistically, competed with FBXW11 for binding SFPQ, preventing FBXW11-mediated k48-linked ubiquitination protein degradation, thereby stabilizing expression. Conclusions Our work confirms critical immunosuppression GC. This novel axis circMAN1A2-SFPQ provides new insights into circRNA-based diagnostic therapeutic strategies.

Language: Английский

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Role of Ubiquitination-driven Metabolisms in Oncogenesis and Cancer Therapy

Seminars in Cancer Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Deubiquitinase USP28 promotes the malignant progression and radio-resistance of hepatocellular carcinoma by stabilizing WDHD1

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Language: Английский

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Post-translational modifications as a key mechanism for herpes simplex virus type I evasion of host innate immunity

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 11, 2025

Herpes simplex virus type 1 (HSV-1) is a DNA that infects humans and establishes long-term latency within the host. Throughout its prolonged interaction with host, HSV-1 evades innate immune system by encoding own proteins. Post-translational modifications (PTMs) of these proteins play crucial roles in their function, activity, interactions other factors modifying specific amino acids, thereby enabling diverse range protein functions. This review explores mechanisms PTMs HSV-1-encoded proteins, such as phosphorylation, ubiquitination, deamidation, SUMOylation, during infection latency. These are essential for suppressing host immunity, facilitating viral replication, elucidating crosstalk among various post-translational modifications.

Language: Английский

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A novel mechanism in regulating drug sensitivity, growth, and apoptosis of bortezomib-resistant multiple myeloma cells: the USP4/KLF2/HMGA2 cascade

Journal of Orthopaedic Surgery and Research, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 1, 2025

Multiple myeloma (MM) is a malignant disorder originating from plasma cells. Bortezomib (BTZ) resistance has become huge obstacle to MM treatment. Herein, we elucidated the action of Kruppel-like factor 2 (KLF2), crucial transcription (TF), on BTZ MM. Two BTZ-resistant cell lines (MM1.S/BTZ and NCI-H929/BTZ) were generated used. KLF2 mRNA was quantified by quantitative PCR, protein expression analyzed immunoblotting. MTT cytotoxicity assay used test sensitivity. Cell growth detected EdU assays. Flow cytometry for apoptosis cycle distribution analyses. The USP4/KLF2 relationship examined Co-IP stability KLF2/HMGA2 interplay confirmed luciferase ChIP Upregulation observed in serum Depletion suppressed enhanced sensitivity MM1.S/BTZ NCI-H929/BTZ Moreover, USP4 increased deubiquitination affected growth, via KLF2. functioned as regulator HMGA2 modulated through HMGA2. Additionally, two lines. Our study demonstrates role USP4/KLF2/HMGA2 cascade regulating cells, providing novel targets improving anti-MM efficacy BTZ.

Language: Английский

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Bioinformatics Based Drug Repurposing Approach for Breast and Gynecological Cancers: RECQL4/FAM13C Genes Address Common Hub Genes and Drugs

Meme sağlığı dergisi/Meme sağlığı dergisi, Journal Year: 2025, Volume and Issue: 21(1), P. 63 - 73

Published: Jan. 2, 2025

Key Points •The aim of the study is to determine genes commonly expressed in both breast and gynaecological cancers identify common hub drug components.In our study,• Primarily, RecQ Like Helicase 4 Family with Sequence Similarity 13 Member C were found be similarly cancer cancers.• Secondly, as a result Drug.MATADOR analysis genes, we have determined these gene/drug interactions such NBN (targeted by Hydroxyurea), EP300 Acetylcarnitine), MAPK14 Salicylate Dibutyryl cyclic AMP).• The drugs associated are not routinely used treatment.• In summary, offer opportunity target repurposing approach which novelty study.It brings together two women's groups (breast cancers) that been clinically targeted literature clinic suggests new candidate drugs/therapeutics.

Language: Английский

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DNA Tetrahedron-Driven Multivalent Proteolysis-Targeting Chimeras: Enhancing Protein Degradation Efficiency and Tumor Targeting

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein interest (POI) ligand and an E3 ligase connected by linker, which can recruit POI ligases simultaneously, thereby inducing the degradation showing great potential in disease treatment. A challenge developing PROTACs is design linkers modification ligands to establish multifunctional platform that enhances efficiency antitumor activity. As programmable modifiable nanomaterial, DNA tetrahedron precisely assemble selectively recognize flexibly adjust distance between molecules, making them ideal linkers. Herein, we developed multivalent PROTAC based on tetrahedron, named AS-TD2-PRO. Using as combined modules targeting tumor cells, recognizing ligases, multiple together. We took undruggable target signal transducer activator transcription 3 (STAT3), associated with etiology progression variety malignant tumors, example this study. AS-TD2-PRO two STAT3 recognition demonstrated good enhancing tumor-specific compared traditional bivalent PROTACs. Furthermore, mouse model, superior therapeutic activity was observed. Overall, tetrahedron-driven both serve proof principle for introduce promising avenue cancer treatment strategies.

Language: Английский

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USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(1), P. e1012843 - e1012843

Published: Jan. 6, 2025

Interferon regulatory factor 3 (IRF3) is a central hub transcription that controls host antiviral innate immunity. The expression and function of IRF3 are tightly regulated by the post-translational modifications. However, it unknown whether unanchored ubiquitination deubiquitination involve modulating immunity against RNA viruses. Here, we find USP5, deubiquitinase (DUB) regulating polyubiquitin, downregulated during anti-RNA viral in type I interferon (IFN-I) receptor (IFNAR)-dependent manner. USP5 further identified to inhibit IRF3-triggered immune responses through its DUB enzyme activity. K48-linked ubiquitin promotes IRF3-driven IFN-β induction IFN-stimulated genes (ISGs) dose-dependent simultaneously removes both K63-linked anchored polyubiquitin chains on IRF3. Our study not only provides evidence regulates but also proposes novel mechanism for DUB-controlled activation, suggesting potential target treatment infectious diseases.

Language: Английский

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Pathological roles of ubiquitination and deubiquitination systems in sepsis-induced myocardial dysfunction

Biomolecules and Biomedicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Sepsis-induced myocardial dysfunction (SIMD) is a severe complication of sepsis, characterized by impaired cardiac function and high mortality rates. Despite significant advances in understanding sepsis pathophysiology, the molecular mechanisms underlying SIMD remain incompletely elucidated. Ubiquitination deubiquitination, critical post-translational modifications (PTMs) regulating protein stability, localization, activity, play pivotal roles cellular processes, such as inflammation, apoptosis, mitochondrial function, calcium handling. Dysregulation these systems has been increasingly implicated pathogenesis SIMD. This review provides comprehensive overview pathological driving SIMD, with focus on classification functions E3 ubiquitin ligases deubiquitinating enzymes (DUBs), their regulatory systems, involvement Dysfunction ubiquitin-proteasome system (UPS), often driven altered activity ligases, accelerates degradation proteins, thereby exacerbating oxidative stress, apoptosis. Concurrently, imbalances DUB disrupt homeostasis, further amplifying injury. Emerging research underscores therapeutic potential targeting systems. Strategies aimed at modulating ligase or restoring balance have shown promise preclinical studies. summarizes current findings ubiquitination deubiquitination pathogenesis, highlights key challenges advancing this field, proposes directions for future research.

Language: Английский

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