Epigenetic Reprogramming in Cancer Metastasis: From Histone Modifications to Therapeutic Vulnerabilities

Cancer metastasis is the leading cause of cancer-related mortality, accounting for more than 90% of cancer deaths worldwide. However, the epigenetic mechanisms governing the metastatic cascade remain incompletely understood. Epigenetic reprogramming, including reversible changes in histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA (ncRNA)-mediated regulation, enables tumor cells to acquire invasive, migratory, stem-like, and immune-evasive characteristics. During epithelial-to-mesenchymal transition (EMT), key epigenetic regulators such as histone deacetylases (HDACs), the Polycomb repressive complex 2 (PRC2) subunit EZH2, lysine-specific demethylase 1 (LSD1/KDM1A), and bromodomain and extraterminal (BET) proteins repress epithelial gene expression while activating mesenchymal transcriptional programs, promoting invasion and dissemination. At distant sites, epigenetic plasticity facilitates metastatic colonization through mesenchymal-to-epithelial transition (MET) and adaptive chromatin remodeling. Because these changes are reversible, they represent attractive therapeutic targets. HDAC, EZH2, LSD1/KDM1A, BET, and DNA methyltransferase (DNMT) inhibitors have shown promise in preclinical models of metastasis, with several advancing through clinical trials. Long non-coding RNAs, particularly HOTAIR, function as epigenetic scaffolds that reinforce metastatic programs, while reciprocal interactions between tumor cells and the tumor microenvironment (TME) drive epigenetic adaptations that promote immune evasion and metastatic progression. In addition, circulating tumor DNA (ctDNA) methylation signatures are emerging as minimally invasive biomarkers for assessing metastatic risk and monitoring treatment. This review summarizes current insights into the epigenetic regulation of cancer metastasis, evaluates emerging epigenetic therapies, and highlights translational opportunities to advance precision anti-metastatic strategies and improve patient outcomes.