UBE2C contributes to malignant phenotypes in clear cell renal cell carcinoma <i>via</i> cell cycle and apoptosis regulation

Background Clear cell renal cell carcinoma (ccRCC) is characterized by aggressive behavior and poor prognosis. Ubiquitin-conjugating enzyme E2C (UBE2C), a key component of the ubiquitin-proteasome system, has been implicated in tumorigenesis; however, its role in ccRCC remains unclear. This study aimed to systematically investigate the clinical relevance, genetic associations, and biological functions of UBE2C in ccRCC. Methods Multi-omics analyses of The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) and Gene Expression Omnibus (GEO) datasets were performed to evaluate UBE2C expression and prognostic significance. Mendelian randomization (MR) analysis was conducted to explore potential genetic associations. Experimental validation was performed using clinical specimens and ccRCC cell lines, including quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), immunofluorescence (IF), functional assays (CCK-8, colony formation, Transwell, and xenograft models), rescue experiments, and western blot analysis. Gene set enrichment analysis (GSEA) and flow cytometry were used to investigate potential mechanisms. Results UBE2C expression was significantly upregulated in ccRCC tissues and was associated with advanced stage, metastasis, high tumor grade, and poor survival (HR = 2.25, 95% CI [1.64–3.09]; P &lt; 0.001). MR analysis suggested a genetic association between elevated serum UBE2C levels and increased ccRCC risk (IVW OR = 1.418, P = 0.010). Functional assays demonstrated that UBE2C knockdown inhibited proliferation, migration, and invasion while promoting apoptosis, whereas UBE2C overexpression enhanced malignant phenotypes. GSEA indicated enrichment of cell cycle and apoptosis-related pathways, which was supported by flow cytometry showing G0/G1 arrest and increased apoptosis in UBE2C-silenced cells. Rescue experiments further showed that re-expression of UBE2C restored proliferative and invasive capacities. Western blot analysis revealed that UBE2C modulated cell cycle and apoptosis-related proteins. Conclusions UBE2C was upregulated in ccRCC and was associated with aggressive clinicopathological features and poor prognosis. Functional, rescue, and protein-level analyses suggested that UBE2C may contribute to malignant phenotypes through regulation of cell cycle progression and apoptosis. These findings indicate that UBE2C may serve as a potential prognostic biomarker and therapeutic target in ccRCC, although further mechanistic studies are required.