UCHL3 depletion inhibits gastric cancer progression and enhances palbociclib sensitivity by regulating the AKT/CCND1 signaling axis via ENO1 ubiquitination

作者：Weiqi Liu, Ling Zhou, Yi Le, Yan He, Juanjuan Zhou, Hongjiao Zhang, Jinbo Zhan, Tingting Hu, Jingru Wang, Yun Lin, Haiming Yu, Jianping Xiong, Ziling Fang, Xiaojun Xiang · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-08153-3 · 被引用次数：1 · 研究领域：Ubiquitin and proteasome pathways、Protein Degradation and Inhibitors、Cancer, Hypoxia, and Metabolism

Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) is a deubiquitinating enzyme involved in various cancers, yet its role in gastric cancer (GC) requires further exploration. This study primarily investigates the expression, function, and mechanisms of UCHL3 in GC. Clinical samples and bioinformatics analysis indicated that UCHL3 is overexpressed in GC tissues compared to adjacent normal tissues, with higher expression levels correlating with worse prognosis. Functional assays demonstrated that UCHL3 promotes GC cell proliferation, invasion, and migration, accelerates cell cycle progression, and induces epithelial-mesenchymal transition (EMT). In vivo studies using a cell line-derived xenograft (CDX) model confirmed that UCHL3 enhances GC proliferation, and its therapeutic potential was validated in patient-derived xenografts (PDX). Mechanistically, transcriptomic analysis and validation experiments identified the AKT/CCND1 signaling pathway as a key mediator of UCHL3-driven GC progression. Co-immunoprecipitation (Co-IP) and liquid chromatography-mass spectrometry identified potential UCHL3-binding proteins, notably the AKT activator ENO1. Molecular docking simulations, Co-IP, and GST-pull down assays further confirmed the interaction, mapping the binding regions between UCHL3 (AA 179-230) and ENO1 (AA 140-434). Cycloheximide (CHX) and in vivo ubiquitination assays demonstrated that UCHL3 deubiquitinates and stabilizes ENO1, thus extending its half-life, while UCHL3 inhibition ...