The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response

Abstract

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.

African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

“…Recently ( 40 ), shared androgen receptor (AR) binding has been established between primary EA prostate cancer samples and prostate cancer cell lines, such as LNCaP, supporting cell line research utility. To complement this, we reasoned that cell lines may reflect primary prostate tissue in an ancestry-dependent manner and therefore we measured the similarity between RC43N cells and nonmalignant AA prostate epithelium, by examining the genomic overlap between chromatin accessibility in cell lines and AR cistrome in primary tissues ( 41 ). These analyses demonstrated that the RC43N and RC43T very significantly overlapped with AA nonmalignant prostate and prostate cancer AR cistromes, but not the EA prostate cancer AR cistrome, and LNCaP most significantly overlapped with the EA prostate cancer AR cistrome ( Supplementary Fig.…”

Diversity, Equity, and Inclusion in Clinical Research: A Path Toward Precision Health for Everyone

“…Even as modern clinical research has brought improvements in medical care across multiple diseases, for minority groups, outcomes continue to lag in numerous health domains. 1 In certain diseases, outcome disparities may be a composite result of genetic and environmental factors, 2,3 and research efforts lacking in diversity leave the medical community catching up to understand that interplay. In the United States specifically, some examples highlight how societal drivers appear to play a major role in health disparities.…”

“…In certain diseases, outcome disparities may be a composite result of genetic and environmental factors, 2,3 and research efforts lacking in diversity leave the medical community catching up to understand that interplay. In the United States specifically, some examples highlight how societal drivers appear to play a major role in health disparities.…”

Exploring new frontiers in prostate cancer research: Report from the 2022 Coffey−Holden prostate cancer academy meeting

“…Where nutrient availability is consistently changing during tumor progression, cancer cells in the TME harness lipid metabolism to support their rapid proliferation, survival, migration, invasion, and metastasis. [46][47][48] Berchuck et al 49 elegantly demonstrated that tumors from AA patients had a distinct differential AR cistrome and greater AR binding intensity at sites enriched for lipid metabolism and immune response genes. Another exciting discovery by Elkenawi et al 50 is on the role of ANPEP in prostate cancer of AA patients.…”