H3K4me3 and H3K27ac Promote ccRCC Proliferation Through the CDC6-EXOSC5 Axis

Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system, with clear cell renal cell carcinoma (ccRCC) accounting for more than 75% of RCC cases and representing the primary cause of mortality in renal cancer patients. CDC6 exhibits oncogenic characteristics and plays a significant role in tumor grading and prognosis prediction. Analysis of The Cancer Genome Atlas (TCGA) data shows that the CDC6 gene is significantly overexpressed in 97.22% (70/72) of paired clinical samples in ccRCC tissues compared to adjacent normal tissues. Consistent with this, elevated CDC6 protein levels were observed across all four paired tumor tissues examined. Functional experiments further confirm that CDC6 expression levels directly influence cellular proliferation, as its knockdown suppresses cell viability by ~60% in CCK-8 assays (p < 0.001) and reduces EdU incorporation by ~50%. Mechanistically, in tumor tissues, CDC6 transcription is epigenetically regulated by histone acetylation and methylation, which in turn modulates downstream effectors, e.g., the exosome complex protein EXOSC5. Our findings indicate that in ccRCC, increased histone H3K4 trimethylation near the CDC6 transcriptional start site enhances its expression. The methyltransferase SETD1A may act as a potential upstream regulator mediating the transcriptional activation of CDC6, thereby driving tumor progression through the regulation of EXOSC5. We have further investigated the relationship between the CDC6-associated gene network and tumor development and clarified the diagnostic and prognostic relevance of the SETD1A–CDC6–EXOSC5 axis in ccRCC. The outcomes of this research are expected to provide novel insights into the pathogenesis of renal cell carcinoma and establish a theoretical foundation for new diagnostic strategies.