USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer

作者：Zhiyong Wang, Cheng‐Ping Yu, Gengchen Xie, Kaixiong Tao, Zhijie Yin, Qing Lv · 发表于：Molecular Medicine · 年份：2025 · DOI：10.1186/s10020-025-01182-w · 被引用次数：9 · 研究领域：Ubiquitin and proteasome pathways、Autophagy in Disease and Therapy、Protein Degradation and Inhibitors

BACKGROUND: Mitophagy, essential for cellular homeostasis, is involved in eliminating damaged mitochondria and is associated with cancer progression and chemoresistance. The specific impact of mitophagy on microsatellite instability-high (MSI-H) colorectal cancer (CRC) is still under investigation. Ubiquitination, a post-translational modification, is essential for controlling protein stability, localization, and function. This study identifies USP14, a deubiquitinating enzyme, as a key regulator of mitophagy in MSI-H CRC. METHODS: A deubiquitinating enzyme (DUBs) siRNA library screening identified USP14 as a key regulator of mitophagy. Tissue samples from patients were analyzed using immunohistochemistry and Western blot. USP14 knockdown cell lines were generated using lentiviral transfection. Protein interactions between USP14 and BAG4 were confirmed by co-immunoprecipitation, while quantitative PCR was used to measure gene expression. Mitochondrial proteins were extracted to analyze mitophagy, and flow cytometry was used to assess apoptosis. Finally, a mouse xenograft model was employed to study USP14's role in tumor growth and oxaliplatin sensitivity. RESULTS: Screening reveals that USP14 inhibits mitophagy and CRC (MSI-H) show high USP14 expression which correlates with poor prognosis. Functional analyses reveal that knocking down USP14 reduces tumor growth, and increases sensitivity to oxaliplatin. Mechanically, USP14 inhibits mitophagy by K48-deubiquitinating and stabi...