Downregulation of class I HLA (HLA-I) impairs immune recognition and surveillance in prostate cancer and is a mechanism of resistance to certain immunotherapies. However, the molecular mechanisms regulating HLA-I loss in prostate cancer have not been fully explored. Epigenetic changes are common in prostate cancer and have been proposed as drivers of prostate cancer progression. Here, we propose that epigenetic mechanisms 1) regulate HLA-I expression in prostate cancer, 2) are targetable by inhibition of epigenetic modifying proteins, and 3) have utility as potential biomarkers in prostate cancer circulating tumor cells (CTCs). We establish this through a comprehensive analysis of HLA-I genomic, epigenomic and gene expression alterations in primary and metastatic human prostate cancer. Genomic alterations were found to be extremely rare in the HLA-I genes in primary and metastatic prostate cancer and were not associated with HLA-I gene expression. Loss of expression of HLA-I genes was associated with increased DNA methylation and histone H3 lysine 27 tri-methylation as well as decreased chromatin accessibility and histone H3 lysine 27 acetylation. We found that epigenetic regulation of the HLA-I genes was targetable by inhibiting DNA methyltransferase (DNMT) and histone deacetylase (HDAC) protein families. DNMT and HDAC inhibition decreased DNA methylation, increased H3 lysine 27 acetylation, and functionally re-expressed HLA-I on the surface of tumor cells. These results suggest the possibility for therapeutic use of epigenetic modifying agents to upregulate HLA-I on tumor cells to promote tumor clearance. Identifying patients who harbor epigenetically regulated HLA-I would allow for more personalized therapy decisions regarding epigenetic and immunotherapies. Described in this thesis is a method we developed for enrichment of methylated DNA from low-input samples, including CTCs. We validate the ability of this assay to detected HLA-I methylation in CTCs with low HLA-I expression, demonstrating the potential for methylated HLA-I as an epigenetic biomarker in prostate cancer.