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Background

Cell division cycle 6 (CDC6) is a key licensing factor for DNA replication in the G1 and S phases. Besides initiating replication, CDC6 also helps establish and maintain the S-M checkpoint, ensuring genomic stability. Emerging evidence highlights its dysregulation in various cancers, implicating CDC6 in tumor progression and therapy resistance. However, a comprehensive pan-cancer analysis evaluating its diagnostic, prognostic and immunomodulatory potential remains lacking, underscoring the need for further investigation.

Methods

By integrating multi-omics datasets from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), cBioPortal, Human Protein Atlas (HPA), UALCAN and SangerBox, we employed systematic bioinformatics approaches to investigate the oncogenic role of CDC6 across multiple cancer types. Our analysis encompassed prognostic associations, mutational landscapes, tumor immune microenvironment (TIME) infiltration patterns and epigenetic regulation via DNA methylation, providing a pan-cancer perspective on CDC6’s potential role in tumorigenesis. In addition, CDC6’s role in melanoma cell proliferation, invasion and migration was experimentally assessed.

Results

Pan-cancer analysis demonstrated CDC6 as a consistently upregulated oncogene across multiple malignancies, exhibiting significantly elevated expression compared to normal tissues. Notably, CDC6 is closely associated with prognosis across various cancer types. Our investigation further revealed robust correlations between CDC6 expression and immune cell infiltration patterns. Epigenetic profiling identified significant associations between CDC6 expression and DNA methylation alterations in nine cancer types. Functional studies validated CDC6’s oncogenic role, where its overexpression significantly promoted cellular proliferation, migration and invasion in melanoma.

Conclusions

Our study demonstrates that CDC6 serves as a crucial oncogenic driver across diverse tumor types, establishing its dual utility as a diagnostic biomarker and independent prognostic indicator. Importantly, we identified a significant correlation between elevated CDC6 expression and specific immune microenvironment alterations, suggesting its potential as a predictive biomarker for immunotherapy response. These findings demonstrate CDC6’s dual role in cancer development and immune regulation, warranting further investigation into its mechanisms and therapeutic potential.