SUMOylation of UBE2C facilitates hepatocellular carcinoma proliferation and invasion via the MAPK pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality worldwide, with limited treatment efficacy due to frequent recurrence and therapeutic resistance. UBE2C, a ubiquitin-conjugating enzyme, has been implicated in various cancers, but its regulatory mechanisms and oncogenic roles in HCC are not well defined. Therefore, the objective of this study was to systematically investigate the expression pattern, biological function, and underlying molecular mechanisms of UBE2C in HCC, with the aim of elucidating its role in tumor progression and exploring its potential as a therapeutic target. METHODS: We integrated transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify genes that are differentially expressed in HCC. UBE2C expression was validated in tissues and cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The functional roles of these genes were assessed via proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) assays. Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) and luciferase assays confirmed that MYBL2 binds to the UBE2C promoter. SUMOylation at UBE2C lysine 18 (K18) was examined using site-directed mutagenesis and coimmunoprecipitation. Downstream signalling was explored through transcriptomic profiling, pathway enrichment, and MAPK pathway activity analysis. Rescue experiments were performed with the MAPK inhibitor trametinib. RESULTS: UBE2C was highly expressed in HCC and correlated with poor prognosis. Knockdown of UBE2C suppressed cell proliferation, migration, and EMT. MYBL2 transcriptionally activated UBE2C, whereas UBC9-mediated SUMOylation at K18 increased its protein stability. UBE2C overexpression activated the MAPK signalling cascade by upregulating PRKCB and PLCG2 expression, leading to increased phosphorylation of RAF, MEK, and ERK. MAPK inhibition attenuated UBE2C-induced oncogenic effects. CONCLUSIONS: We reveal a novel oncogenic axis in which MYBL2 and SUMOylation cooperatively increase UBE2C expression and stability, promoting HCC progression via MAPK pathway activation. Targeting the MYBL2/UBE2C/MAPK axis represents a potential therapeutic strategy for treating HCC.