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A novel USP4 inhibitor suppresses colorectal cancer stemness and enhances chemotherapy sensitivity by promoting the degradation of β-catenin and Twist1

ABSTRACT: The high mortality rate of metastasis colorectal cancer (CRC) is mainly due to chemotherapy resistance. Evidence implicates cancer stem cells (CSCs) play essential roles in chemoresistance. The deubiquitinating enzymes are vital regulators in both CSCs maintenance. Targeting deubiquitinase might be potential strategies to clear CSCs and overcome chemotherapy resistance. Here, we demonstrated that ubiquitin-specific peptidase 4 (USP4) is a key regulator of cancer stemness by stabilizing β-catenin and Twist1 proteins in CRC cells. Additionally, U4-I05, a novel natural small molecule that targets the enzyme activity of USP4 is characterized. U4-I05 binds to the catalytic domain of USP4 at nanomolar concentrations, resulting in the proteasome-mediated degradation of β-catenin and Twist1. Furthermore, U4-I05 attenuated CSC features and augmented sensitivity to oxaliplatin and 5-fluorouracil. In a genetically engineered CRC mouse model, U4-I05 inhibited tumor metastasis and prolonged survival. Overall, this study identifies U4-I05 as a USP4 inhibitor that has meaningful efficacy toward CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272835 | GEO | 2025/01/29

REPOSITORIES: GEO

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Diverse Targets of β-catenin during the Epithelial-Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse

Project description:Wnt signaling contributes to the reprogramming and maintenance of cancer stem cell (CSC) states that is activated by the epithelial-mesenchymal transition (EMT) program. However, the mechanistic relationship between the EMT and Wnt pathway in CSCs remains unclear. Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) indicated that EMT induces a switch from the β-catenin/E-cadherin/Sox15 complex to the β-catenin/Twist1/TCF4 complex, which then binds to CSC-related gene promoters. In tandem co-IP and re-ChIP experiments using epithelial-type cells, Sox15 associated with the β-catenin/E-cadherin complex and then bound to the proximal promoter region of CASP3, consequently resulting in Twist1 cleavage and negatively regulating the β-catenin–elicited promotion of the CSC phenotype. During the EMT, Twist1 in complex with β-catenin enhanced β-catenin/TCF4 transcriptional activity, which includes binding to the proximal promoter region of ABCG2, a marker of CSCs. For clinical application, the five-gene signature nuclear β-cateninHigh/nuclear Twist1High/E-cadherinLow/Sox15Low/CD133High may be a valuable prognostic marker in patients with human lung cancer.

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