ArticleJournal of translational medicine2025
A novel USP4 inhibitor that suppresses colorectal cancer stemness by promoting β-catenin and Twist1 degradation.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Balancing Ubiquitination and Deubiquitination in Apoptotic Protein Stability and Cancer Cell Survival.International journal of molecular sciences · 2026Review
- USP4 promotes non-small cell lung cancer tumorigenesis by antagonizing CNOT4-mediated degradation of PAF1.Respiratory research · 2026Article
- Regulatory roles of five key USP family deubiquitinases in cancer: from mechanisms to targeted therapy advances.Frontiers in pharmacology · 2026Review
- Integrated multi-omics analysis identifies key biomarkers associated with post-translational modifications and RNA methylation in clear cell renal cell carcinoma.Discover oncology · 2025Article
- Ubiquitin-specific proteases as key regulators in the malignant progression and therapy resistance of colorectal cancer: current insights and future perspectives.Discover oncology · 2025Review
- AKT and DUBs: a bidirectional relationship.Cellular & molecular biology letters · 2025Review
- Role of Ubiquitin-regulated EMT in Cancer Metastasis and Chemoresistance.International journal of biological sciences · 2025Review
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Authors and funding
13 authors.
Funding
Abstract
backgroundThe high mortality rate of metastatic colorectal cancer (CRC) is primarily attributed to resistance to chemotherapy, where cancer stem cells (CSCs) play a crucial role. Deubiquitinating enzymes are essential regulators of CSC maintenance, making them potential targets for eliminating CSCs and overcoming chemotherapy resistance. This study aims to identify key deubiquitinating enzymes regulating CSCs and drug resistance of CRC.
methodsRNA sequencing was performed to examine the mRNA expression of known deubiquitinating enzymes in CRC tissues from patients with alternate response to chemotherapy. Gain- and loss-of-function experiments were performed to evaluate the function of USP4 in regulation of stemness and drug sensitivity in CRC. High-throughput virtual screening and target management assays were conducted to identify small molecule inhibitor targeting USP4. Cell lines, organoids and animal models were used to evaluate the function of USP4 and its small molecule inhibitor in stemness and chemotherapy response.
resultsThe expression of USP4 was significantly elevated in CRC samples from progressive disease (PD) or stable disease (SD) patients compared to partial response (PR) specimen. USP4 promoted stemness by stabilizing the β-catenin and Twist1 proteins in CRC cells. A natural small molecule product U4-I05 diminished the stem-like features of CSCs and enhanced their sensitivity to oxaliplatin and 5-fluorouracil by targeting inhibition of its deubiquitinating enzyme activity through binding the catalytic domain of USP4 (311 cysteine site) at nanomolar concentrations, triggering proteasome-mediated degradation of β-catenin and Twist1. Treatment with U4-I05 also inhibited tumor metastasis and extended survival in a genetically engineered CRC mouse model.
conclusionsThis study identifies U4-I05 as a USP4 inhibitor with significant therapeutic efficacy against CRC, offering a promising avenue for the development of new treatments targeting cancer stemness and chemotherapy resistance.
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