ArticleMolecular medicine (Cambridge, Mass.)2025
USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer.
Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
- The microbiome-mitochondria axis: the context-dependent role of urolithin A in aging and cancer via mitophagy.Molecular biology reports · 2026Review
- Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.iScience · 2026Review
- Natural polysaccharides targeting mitochondrial function for colorectal cancer prevention and treatment: mechanisms and nano-delivery strategies.Chinese medicine · 2026Review
- Emerging regulatory model of Ubiquitin-Specific Proteases 14 in cancer: from canonical oncogenesis to TME modulation, therapeutic resistance, and non-canonical activities.Journal of translational medicine · 2026Review
- Advances in mitochondrial-targeted colorectal cancer therapy: Mechanistic insights and clinical translation.iScience · 2026Review
- Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer.Frontiers in immunology · 2026Review
- RHOT1‑mediated molecular mechanism of mitochondrial dysfunction and its phenotypic effects on gastric cancer cells.International journal of oncology · 2025Article
- Mitophagy in the mechanisms of treatment resistance in solid tumors.Oncology reviews · 2025Review
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Abstract
backgroundMitophagy, 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.
methodsA 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.
resultsScreening 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 stabilizing BAG4 at K403, which prevents the recruitment of Parkin to damaged mitochondria. The significant clinical relevance of USP14, BAG4, and PRKN are proved in tumor tissues.
conclusionsThe study highlights the USP14/BAG4/PRKN axis as a critical pathway in CRC (MSI-H), suggesting that targeting USP14 could inhibit tumor progression and improve chemotherapeutic outcomes. These findings underscore the importance of ubiquitination and mitophagy in cancer biology, indicating a potential therapeutic target for MSI-H CRC.
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