Epigenetic reprogramming in Urothelial bladder cancer: mechanisms, biomarkers, and therapeutic opportunities

Urothelial bladder cancer (UBC) is a molecularly heterogeneous malignancy characterized by frequent recurrence, variable progression, and treatment resistance. In addition to recurrent genetic alterations, dysregulation of chromatin remodeling, histone modifications, DNA methylation, and enhancer activity contributes to the biological diversity of UBC. This narrative review critically evaluates the role of epigenetic reprogramming in UBC and integrates mechanistic evidence with biomarker development and therapeutic investigation. Recurrent alterations involving ARID1A, KDM6A, KMT2C/KMT2D, EP300, and CREBBP can modify chromatin accessibility and transcriptional programs, although the functional consequences and strength of causal evidence vary among regulators. Preclinical studies have identified therapeutically relevant dependencies, including the relationship between KDM6A loss, PRC2-mediated repression, and EZH2 inhibition, but clinical validation of most epigenetic targets remains limited. DNA methylation represents the most extensively investigated epigenetic biomarker class in UBC. Urine-based methylation assays have shown encouraging diagnostic performance, whereas plasma cell-free DNA methylation remains an emerging approach requiring further prospective validation. Clinical studies of epigenetic therapies have produced mixed results, emphasizing the need to distinguish biological rationale from demonstrated therapeutic efficacy. Collectively, current evidence supports epigenetic alterations as important contributors to UBC biology while highlighting the need for functional validation, biomarker-selected trials, and longitudinal epigenomic studies before routine clinical implementation.