African American (AA) men are more likely to be diagnosed with and die from prostate cancer (PCa) than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in PCa, little is known about the contribution of epigenetics to observed racial disparities. We performed AR ChIP-seq on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA PCa are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and increased lipid levels in AA PCa. In a metastatic prostate cancer cohort, upregulated lipid metabolism associated with poor prognosis. These findings offer the first insights into ancestry-specific differences in the PCa AR cistrome. The data suggest a model whereby increased androgen signaling may contribute to higher levels of lipid metabolism, immune response, and cytokine signaling in AA prostate tumors. Given the association of upregulated lipogenesis with PCa progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of PCa observed in AA men.

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