Epigenetic alterations in cancer metastasis: molecular mechanisms and implications for precision oncology

Metastasis is a complex, multistep process that underlies the majority of cancer-related deaths and is increasingly recognized as a consequence of dynamic epigenetic reprogramming rather than solely genetic alterations. Epigenetic mechanisms enable stable yet reversible changes in gene expression that drive cellular plasticity throughout the metastatic cascade, including epithelial-mesenchymal transition (EMT), intravasation, survival as circulating tumor cells, extravasation, dormancy, and metastatic colonization. In this review, we provide an integrated overview of the molecular epigenetic mechanisms regulating cancer metastasis, with particular emphasis on DNA methylation, histone post-translational modifications, chromatin remodeling complexes, and non-coding RNAs. We discuss how these epigenetic regulators interact with key EMT-associated signaling pathways to control phenotypic plasticity, anoikis resistance, and metastatic niche adaptation. In addition, emerging evidence supports the clinical relevance of metastasis-associated epigenetic alterations, including DNA methylation signatures, histone modification patterns, and non-coding RNA profiles, as promising diagnostic and prognostic biomarkers. Selected examples such as aberrant CDH1 promoter methylation, miR-200 family dysregulation, and EZH2-mediated chromatin remodeling illustrate their potential utility in patient stratification and therapeutic targeting. A deeper mechanistic understanding of epigenetic regulation across metastatic stages may facilitate the development of clinically actionable biomarkers and combination therapies in precision oncology.