USP3 promotes clear cell renal cell carcinoma progression by stabilizing MYC and enhancing glycolysis

• Published in: Biochimica et biophysica acta. General subjects Vol. 1869; no. 6; p. 130801
• Main Authors: Xiao, Zhiliang, Wang, Yuan, Pan, Dehua, Liu, Xin, Gan, Jin, Huang, Liang, Feng, Yan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2025
• Subjects: Apoptosis; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; ccRCC; Cell Line, Tumor; Cell Movement; Cell Proliferation - genetics; Deubiquitinase; Disease Progression; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; MYC; Protein Stability; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism; USP3; ccRCC; Deubiquitinase; USP3; MYC; Apoptosis
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2025.130801

Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal malignancy, and the deubiquitinase USP3 has been implicated as a critical factor in tumor biology. However, the precise mechanisms by which USP3 contributes to ccRCC progression remain unclear. This study investigates the role of USP3 in ccRCC and elucidates its underlying molecular mechanisms. Data from TCGA and GTEx databases showed elevated USP3 expression in ccRCC tissues and cell lines compared to normal renal tissues. Further analysis using qPCR and Western blot confirmed this upregulation in ccRCC cell lines. Functional assays revealed that silencing USP3 significantly impaired cell proliferation, migration, and invasion, while promoting apoptosis. Additionally, co-immunoprecipitation assays demonstrated an interaction between USP3 and MYC, with subsequent ubiquitination assays showing that USP3 regulates MYC stability. USP3 depletion also led to alterations in glycolysis-related gene expression, which could be partially reversed by MYC overexpression. These findings suggest that USP3 modulates ccRCC progression by stabilizing MYC, highlighting its potential as a therapeutic target in ccRCC treatment. •USP3 is significantly upregulated in ccRCC: Bioinformatics and experimental analyses reveal elevated USP3 expression in ccRCC tissues and cell lines.•USP3 sustains MYC stability: Co-IP and ubiquitination assays show USP3 binds to MYC, reduces its ubiquitination, and extends its half-life.•Metabolic reprogramming via MYC: Stabilized MYC enhances glycolysis, evidenced by increased glucose uptake, lactate production, and glycolytic enzyme expression.•Functional impact on tumor phenotype: USP3 knockdown suppresses proliferation, migration, and invasion, while promoting apoptosis in ccRCC cells.•Therapeutic implications: Targeting USP3-mediated MYC stabilization may disrupt glycolysis and provide a novel strategy to inhibit ccRCC progression.