Ubiquitin-specific proteases: From biological functions to potential therapeutic applications in gastric cancer

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 173, P. 116323 - 116323

Published: Feb. 23, 2024

Deubiquitination, a post-translational modification regulated by deubiquitinases, is essential for cancer initiation and progression. Ubiquitin-specific proteases (USPs) are elements of the deubiquitinase family, overexpressed in gastric (GC). Through regulation several signaling pathways, such as Wnt/β-Catenin nuclear factor-κB signaling, promotion expression deubiquitination- stabilization-associated proteins, USPs promote proliferation, metastasis, invasion, epithelial-mesenchymal transition GC. In addition, closely related to clinicopathological features, patient prognosis, chemotherapy resistance. therefore could be used prognostic biomarkers. USP targeting small molecule inhibitors have demonstrated strong anticancer activity. However, they not yet been tested clinic. This article provides an overview latest fundamental research on GC, aiming enhance understanding how contribute GC progression, identifying possible targets treatment improve survival.

Language: Английский

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Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(4), P. 1624 - 1643

Published: Jan. 17, 2024

HMGA2, a pivotal transcription factor, functions as versatile regulator implicated in the progression of diverse aggressive malignancies. In this study, mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with and USP48 identified deubiquitinating enzyme HMGA2. The enforced expression significantly increased HMGA2 protein levels by inhibiting its degradation, while deprivation promoted thereby suppressing tumor invasion metastasis. We discovered undergoes SUMOylation at lysine 258, which enhances binding affinity Through subsequent phenotypic screening small molecules, we DUB-IN-2 remarkably potent pharmacological inhibitor USP48. Interestingly, small-molecule targeting induces destabilization Clinically, upregulation or cancerous tissues is indicative poor prognosis for patients colorectal cancer (CRC). Collectively, our study not only elucidates regulatory mechanism DUBs involved stability validates potential therapeutic target CRC, but also identifies promising candidate CRC treatment.

Language: Английский

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USP33 promotes pancreatic cancer malignant phenotype through the regulation of TGFBR2/TGFβ signaling pathway

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(6)

Published: June 15, 2023

Abstract Pancreatic cancer (PC) ranked fourth among cancer-related death worldwide with a survival rate less than 5%. The abnormal proliferation and distant metastasis are major obstacles for the diagnosis treatment of pancreatic cancer, therefore, it is urgent researchers to uncover molecular mechanisms underlying PC metastasis. In current study, we found that USP33, member deubiquitinating enzyme family, was upregulated samples cells, meanwhile, high expression USP33 correlated poor prognosis patients. Function experiments revealed overexpression promoted proliferation, migration invasion cells while inhibition in exhibited opposite effect. mass spectrum luciferase complementation assay screened TGFBR2 as potential binding protein USP33. Mechanistically, triggered deubiquitination prevented its degradation by lysosome, therefore accumulation cell membrane eventually contributed sustained activation TGF-β signaling. Moreover, our results targeted gene ZEB1 transcription conclusion, study through positive feedback loop signaling pathway. this suggested may serve prognostic therapeutic target PC.

Language: Английский

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USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(3)

Published: March 26, 2024

Ubiquitin-specific protease 3 (USP3) plays an important role in the progression of various tumors. However, USP3 osteosarcoma (OS) remains poorly understood. The aim this study was to explore biological function OS and underlying molecular mechanism. We found that had higher expression compared with normal bone tissue, high associated poor prognosis patients OS. Overexpression significantly increased cell proliferation, migration, invasion. Mechanistically, led activation PI3K/AKT signaling pathway by binding EPHA2 then reducing its protein degradation. Notably, truncation mutant USP3-F2 (159-520) interacted EPHA2, amino acid 203 play process. And knockdown reversed pro-tumour effects USP3-upregulating. Thus, our indicates USP3/EPHA2 axis may be a novel potential target for treatment.

Language: Английский

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USP3: Key deubiquitylation enzyme in human diseases

Cancer Science, Journal Year: 2024, Volume and Issue: 115(7), P. 2094 - 2106

Published: April 23, 2024

Ubiquitination and deubiquitylation are pivotal posttranslational modifications essential for regulating cellular protein homeostasis implicated in the development of human diseases. Ubiquitin-specific protease 3 (USP3), a member ubiquitin-specific family, serves as key enzyme, playing critical role diverse processes including DNA damage response, cell cycle regulation, carcinogenesis, tumor proliferation, migration, invasion. Despite notable research efforts, our current understanding intricate context-dependent regulatory networks governing USP3 remains incomplete. This review aims to comprehensively synthesize existing published works on USP3, elucidating its multifaceted roles, functions, mechanisms, while offering insights future investigations. By delving into complexities this strives provide foundation more nuanced specific roles various processes. Furthermore, exploration USP3's may uncover novel therapeutic strategies targeting enzyme diseases, thereby holding promising clinical implications. Overall, an in-depth comprehension functions pathways is crucial advancing knowledge developing targeted approaches

Language: Английский

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USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(11)

Published: Nov. 5, 2024

Abstract The chromatin-remodeling enzyme SMARCA5 plays a key role in DNA-templated events including transcription, DNA replication, and repair. Loss of function the can cause neurodevelopmental disorder Williams syndrome. However, molecular mechanism underlying regulation prostate cancer remains largely elusive. Here, we report that deubiquitinating USP3 directly interacts with removes K63-linked polyubiquitination to maintain its stability, which promotes damage repair chemotherapy resistance. Depletion or promoted PCa cells sensitive docetaxel overexpression restored resistance treatment silenced vitro vivo. Clinically, was significantly up-regulated tissues positively associated expression. Collectively, our findings uncover novel for USP3-SMARCA5 axis regulating DSB an important response human cancers, highlighting targeting could be valuable strategy treat USP3/SMARCA5-overexpressing chemotherapy-resistant patients improve drug treatment.

Language: Английский

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Identification of Cancer Driver Genes by Integrating Multiomics Data with Graph Neural Networks

Metabolites, Journal Year: 2023, Volume and Issue: 13(3), P. 339 - 339

Published: Feb. 24, 2023

Cancer is a heterogeneous disease that driven by the accumulation of both genetic and nongenetic alterations, so integrating multiomics data extracting effective information from them expected to be an way predict cancer driver genes. In this paper, we first generate comprehensive instructive features for each gene genomic, epigenomic, transcriptomic levels together with protein-protein interaction (PPI)-networks-derived attributes then propose novel semisupervised deep graph learning framework GGraphSAGE genes according impact alterations on biological system. When applied eight tumor types, experimental results suggest outperforms several state-of-the-art computational methods identification. Moreover, it broadens our current understanding level identifies specific type rather than pan-cancer. We expect open new avenues in precision medicine even further drivers other complex diseases.

Language: Английский

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ELF5 drives angiogenesis suppression though stabilizing WDTC1 in renal cell carcinoma

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Nov. 18, 2023

Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system. Angiogenesis main contributing factor for tumorigenesis. E74-like transcription 5 (ELF5) has been verified to participate in progression different cancers and can regulate angiogenesis. This study was aimed explore functions ELF5 RCC.Bioinformatics tools were used predict expression RCC. RT-qPCR applied testing RCC cells. Cell behaviors evaluated by colony formation, CCK-8, transwell assays. The tube formation assay determining Methylation-specific PCR (MSP) utilized measuring methylation level ChIP luciferase reporter assays assessing binding ubiquitin-specific protease 3 (USP3). Co-IP GST pull-down detecting interaction WD40 tetratricopeptide repeats 1 (WDTC1) USP3. Ubiquitination WDTC1 determined ubiquitination assay.ELF5 lowly expressed cells tissues. High notably suppressed proliferative, migratory, invasive capabilities, inhibited growth mice overexpression. highly methylated samples, DNA methyltransferases (DNMTs) promote hypermethylation further proved transcriptionally activate USP3 Moreover, ubiquitination. USP3-mediated stabilization. Additionally, silencing reversed overexpression on progression.Downregulation due inhibits development though USP3/WDTC1axis

Language: Английский

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Dysregulation of deubiquitinylases: a linchpin of gastrointestinal diseases

Trends in Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Ubiquitin-Specific Protease Inhibitors for Cancer Therapy: Recent Advances and Future Prospects

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 240 - 240

Published: Feb. 7, 2025

Cancer management has traditionally depended on chemotherapy as the mainstay of treatment; however, recent advancements in targeted therapies and immunotherapies have offered new options. Ubiquitin-specific proteases (USPs) emerged promising therapeutic targets cancer treatment due to their crucial roles regulating protein homeostasis various essential cellular processes. This review covers following: (1) structural functional characteristics USPs, highlighting involvement key cancer-related pathways, (2) discovery, chemical structures, mechanisms action, potential clinical implications USP inhibitors therapy. Particular attention is given role enhancing immunotherapy, e.g., modulation tumor microenvironment, effect regulatory T cell function, influence immune checkpoint pathways. Furthermore, this summarizes current progress challenges trials involving We also discuss complexities achieving target selectivity, ongoing efforts develop more specific potent inhibitors, overcome drug resistance synergize with existing treatments. finally provide a perspective future directions targeting including for personalized medicine based gene mutations, underscoring significant treatment. By elucidating progress, applications, we hope that could serve useful resource both basic scientists clinicians field therapeutics.

Language: Английский

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