USP4‐Deubiquitinated PGAM5 Regulates Mitochondrial Dynamics in the Progression of Esophageal Squamous Cell Carcinoma

Nov 2, 2025Molecular carcinogenesis

How a Protein Modification Controls Mitochondria Changes in Esophageal Cancer Growth

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Abstract

High expression of USP4 and phosphoglycerate mutase 5 (PGAM5) was observed in esophageal squamous cell carcinoma (ESCC) tissues.

USP4 maintains PGAM5 stability by removing K48-linked ubiquitin chains.
Knockdown of PGAM5 reduced the aggressive behaviors of ESCC cells and altered key mitochondrial functions.
Overexpression of USP4 led to increased mitochondrial membrane potential and Bcl2 levels, while decreasing apoptotic markers.
In vivo studies indicated that ectopic USP4 accelerated tumor growth in mice, which was mitigated by PGAM5 knockdown.
The findings suggest that USP4 may promote cell growth and excessive mitophagy in ESCC.

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This study explored the effect of ubiquitin-specific protease 4 (USP4) on mitochondrial dynamics in esophageal squamous cell carcinoma (ESCC). USP4 and phosphoglycerate mutase 5 (PGAM5) expression in ESCC tissues was measured. ESCC cells were subjected to gain- and loss-of-function experiments, followed by examinations of proliferation, invasion, migration, apoptosis, light chain 3 (LC3), P62, Bcl2-associated X (Bax), B-cell lymphoma 2 (Bcl2), Cytochrome c (CytC), caspase3, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS), and ROS. An in vivo tumor formation model of ESCC was established for in vivo verification. The relationship between USP4 and PGAM5 was analyzed. USP4 and PGAM5 expression was high in ESCC tissues. Mechanistically, USP4 eliminated K48-linked ubiquitin chains to maintain PGAM5 stability. PGAM5 knockdown impaired malignant behaviors of ESCC cells, reduced LC-3I-to-LC-3II conversion, increased mtROS, ROS, and P62 levels, activated the caspase-dependent mitochondrial pathway, and decreased MMP. Overexpressing USP4 increased MMP and Bcl2 expression while lowering Bax, CytoC, cleaved caspase3, and mtROS levels in ESCC cells, which was nullified by PGAM5 knockdown. Ectopic USP4 accelerated tumor growth in mice, which was reversed by PGAM5 knockdown. Collectively, USP4 promotes cell growth and excessive mitophagy in ESCC by stabilizing PGAM5.

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USP4‐Deubiquitinated PGAM5 Regulates Mitochondrial Dynamics in the Progression of Esophageal Squamous Cell Carcinoma

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