|The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response.
|Year of Publication
|Berchuck JE, Adib E, Alaiwi SAbou, Dash AK, Shin JNa, Lowder D, McColl C, Castro P, Carelli R, Benedetti E, Deng J, Robertson M, Baca SC, Bell C, McClure HM, Zarif TEl, Davidsohn MP, Lakshminarayanan G, Rizwan K, Skapura DG, Grimm SL, Davis CM, Ehli EA, Kelleher KM, Seo J-H, Mitsiades N, Coarfa C, Pomerantz MM, Loda M, Ittmann M, Freedman ML, Kaochar S
|2022 08 16
|African Americans, Humans, Immunity, Lipid Metabolism, Male, Prostatic Neoplasms, Receptors, Androgen, Up-Regulation
African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer 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 prostate cancer. 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 prostate cancer 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 prostate cancer progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of prostate cancer observed in AA men.
SIGNIFICANCE: With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.
|T32 GM136554 / GM / NIGMS NIH HHS / United States
T32 GM008231 / GM / NIGMS NIH HHS / United States
R01 CA131945 / CA / NCI NIH HHS / United States
U54 CA233223 / CA / NCI NIH HHS / United States
Massimo Loda, M.D.