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

African American (AA) prostate cancer associates with vitamin D3 de-ficiency, but vitamin D receptor (VDR) genomic actions have not been investigated in this context. We undertook VDR proteogenomic analyses in European American (EA) and AA prostate cell lines and four clini-cal cohorts. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analyses revealed that nonmalignant AA RC43N prostate cells displayed the greatest dynamic protein content in the VDR com-plex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1 & alpha;,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed signif-icant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1 & alpha;,25(OH)2D3-dependent transcriptome. These VDR functions were significantly corrupted in the isogenic AA RC43T prostate cancer cells, and significantly distinct from EA cell models. We identified reduced expression of the chromatin remodeler, BAZ1A, in three AA prostate cancer cohorts as well as RC43T compared with RC43N. Restored BAZ1A ex-pression significantly increased 1 & alpha;,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clini-cal impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA pa-tients with prostate cancer, the genes bound by VDR and/or associated with 1 & alpha;,25(OH)2D3-dependent open chromatin (i) predicted progression from high-grade prostatic intraepithelial neoplasia to prostate cancer; (ii) responded to vitamin D3 supplementation in prostate cancer tumors; (iii) differentially responded to 25(OH)D3 serum levels. Finally, partial correla-tion analyses established that BAZ1A and components of the VDR complex identified by RIME significantly strengthened the correlation between VDR and target genes in AA prostate cancer only. Therefore, VDR transcrip-tional control is most potent in AA prostate cells and distorted through a BAZ1A-dependent control of VDR function.Significance: Our study identified that genomic ancestry drives the VDR complex composition, genomic distribution, and transcriptional function, and is disrupted by BAZ1A and illustrates a novel driver for AA prostate cancer.

Automated summary

African American prostate cancer is associated with vitamin D3 deficiency, and VDR genomic actions play a significant role in this context. The study found that nonmalignant AA prostate cells exhibited the highest protein content in the VDR complex, and had increased chromatin accessibility and enhancer-enriched VDR cistrome in response to 1,25(OH)2D3. However, these VDR functions were disrupted in AA prostate cancer cells due to reduced expression of the chromatin remodeler BAZ1A. The clinical impact of VDR cistrome-transcriptome relationships was also demonstrated in African American patients with prostate cancer. Rating: 8/10.