A novel USP4 inhibitor that suppresses colorectal cancer stemness by promoting β-catenin and Twist1 degradation

作者：Fengtian Li, Yi Zhou, Xinyue Lin, Yaxin Zhang, Qingyong Hu, Enen Zhao, H.‐B. Li, Xingyan Pan, Feng Shu, Kun Zhang, Chengmei Huang, Na Tang, Wenting Liao · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-024-06001-0 · 被引用次数：10 · 研究领域：Ubiquitin and proteasome pathways、Cancer Cells and Metastasis、Microtubule and mitosis dynamics

BACKGROUND: The 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. METHODS: RNA 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. RESULTS: The 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 deubiquitina...