Present and Future of Epigenetics in Prostate Cancer: Therapeutic Opportunities and Translational Approaches

Prostate cancer (PCa) is among the most diagnosed malignancies worldwide and is a leading cause of cancer-related mortality, with clinical management complicated by biological heterogeneity. Epigenetic alterations (including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation) are increasingly recognized as key drivers of PCa initiation, progression, and therapeutic resistance. In early-stage disease, for example, the hypermethylation of promoter regions silencing tumor suppressor genes represents one of the earliest oncogenic events. During progression to castration-resistance, epigenetic mechanisms modulate androgen receptor signaling through chromatin remodeling complexes, DNA demethylation regulators, and histone-modifying enzymes. In therapy-induced neuroendocrine prostate cancer (t-NEPC), an even more aggressive form of PCa, dynamic epigenetic reprogramming, driven by chromatin-modifying enzymes and metabolic-epigenetic crosstalk, underlies lineage plasticity and transdifferentiation from adenocarcinoma. Pharmacological targeting of epigenetic regulators has been explored across multiple drug classes and clinical settings, though development remains limited compared to other malignancies; certain inhibitor classes are more clinically advanced than others, while dedicated trials in particularly NEPC remain scarce. Epigenetic biomarkers, detectable in tissue, blood, and urine, show promise for diagnosis, prognosis, and risk stratification, with multi-marker signatures outperforming individual markers. Translational advances (including bisulfite-based methylation assays, liquid biopsy platforms, single-cell/multi-region sequencing, and transcriptomic classifiers) are progressively enabling clinical application. Despite this progress, intratumoral heterogeneity, lack of standardization, and insufficient prospective validation continue to hinder routine implementation, underscoring the need for integrated multi-omic approaches in future PCa precision medicine.