Epigenetic Drivers of Resistance to Androgen Deprivation in Prostate Cancer: A Critical Appraisal of Mechanisms, Evidence Quality and Therapeutic Translation

Abstract

Androgen deprivation remains the therapeutic foundation of advanced prostate cancer, yet the durability of response is limited and progression to castration-resistant disease is close to universal. Genomic explanations centred on androgen receptor amplification, point mutation and splice variation account for only part of this failure, and attention has shifted towards chromatin-based and other epigenetic mechanisms that permit tumour cells to rewire transcription without acquiring new coding mutations. This review examines, critically rather than descriptively, the evidence that epigenetic processes act as drivers of resistance to androgen deprivation, and evaluates how securely that evidence supports the mechanistic and therapeutic claims made on its behalf. Literature was identified through structured searching of open biomedical and multidisciplinary scholarly sources, supplemented by backward and forward citation tracking and by checks for corrections and retractions. Sources were appraised for design adequacy, model relevance, independence of replication and the strength of the link between the observation and the resistance phenotype. Evidence was organised around mechanisms and controversies rather than around individual publications. Four themes structure the synthesis. The first concerns reprogramming of androgen receptor chromatin occupancy through pioneer factors, enhancer amplification and chromatin remodelling complexes, where the evidence for causal contribution is comparatively strong but strongly model dependent. The second concerns the repressive axis formed by polycomb-mediated histone methylation and DNA methylation, where canonical and non-canonical enzyme functions have been conflated in ways that complicate therapeutic inference. The third concerns lineage plasticity and neuroendocrine transdifferentiation, where competing transdifferentiation and clonal selection accounts remain incompletely resolved. The fourth concerns clinical translation, where preclinical effect sizes have not been reproduced in trials of histone deacetylase, bromodomain and extraterminal domain, or enhancer of zeste homologue 2 inhibitors. Confidence is highest for the proposition that epigenetic reconfiguration accompanies and enables resistance, and considerably lower for the proposition that any single epigenetic enzyme is a dominant and druggable driver. The most defensible priorities are patient-level longitudinal epigenomic sampling, biomarker-guided rather than unselected trial design, and mechanistic work that separates enzymatic from scaffolding functions of chromatin regulators.