Stage-dependent EZH2 methylation correlates with immune polarization, metabolic suppression, and unfavorable outcomes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, continues to pose significant clinical challenges globally. Enhancer of Zeste Homolog 2 (EZH2), a central component of the Polycomb Repressive Complex 2 (PRC2), possesses histone methyltransferase activity through its SET domain and is frequently overexpressed in various cancers. Nevertheless, the precise role and regulatory mechanisms of EZH2 in HCC remain inadequately defined. In this research, we evaluated the expression levels of EZH2 at the mRNA and protein stages in HCC samples and examined their correlation with clinical features and patient survival outcomes. Patients were categorized into early- and late-stage groups based on tumor grade. Our methylation analyses pinpointed two specific CpG sites within the EZH2 gene, cg08558971 and cg18416251, which exhibited inverse methylation patterns between tumor stages. One patient subgroup displayed high methylation at cg08558971 during early-stage disease and reduced methylation at cg18416251 during late-stage disease, while another subgroup demonstrated the reverse pattern. Further pathway enrichment analysis suggested these methylation variations might influence enhanced T-cell differentiation and suppress metabolic pathways. Additionally, correlation analyses consistently linked EZH2 expression to genes involved in these immune and metabolic pathways. Collectively, our data propose that EZH2 could serve as a meaningful independent prognostic biomarker for HCC, regulated by stage-dependent epigenetic changes that may drive tumor progression by modulating immune response and cellular metabolism.