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

Abstract

African American (AA) prostate cancer associates with vitamin D3 deficiency, 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 clinical 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 complex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1α,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,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 expression significantly increased 1α,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clinical impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA patients with prostate cancer, the genes bound by VDR and/or associated with 1α,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 correlation 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 transcriptional 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.

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer

“…Beyond direct epigenetic regulation within promoter regions, gene expression changes were also contributed by reprogrammed enhancers looped to these promoters. Consistent with the conclusion that OC2 has the capability to bind to closed chromatin and promote chromatin accessibility, we show that OC2 interacts with SMARCA4 and SMARCA5, which are important components of CRCs that modify chromatin architecture to allow TF access to condensed chromatin [45,46]. Inactivation of CHD1, another chromatin remodeler, has been shown to promote the emergence of tumor heterogeneity and enzalutamide resistance [47].…”

Epigenetic disruption of the RARγ complex impairs its function to bookmark AR enhancer interactions required for enzalutamide sensitivity in prostate cancer

“…To examine how components of the RARγ complex impacted AR gene regulation we used partial correlation analyses to test the impact of coregulators in the RARγ complex on the relationship between AR expression and genes associated with AR bound in active enhancers by using the SU2C cohort of advanced PCa ( Figure 8B ). This demonstrated that several of the coregulators in the RARγ complex, including SSRPI(98) and BAZ1A(95), significantly and positively impacted the strength of the correlations between AR expression and AR enhancer dependent target genes.…”

“…Secondly, we tested if RARγ-dependent augmentation of ChromHMM-categorized AR cistrome significantly impacted the dependent-transcriptome relationships(21) by applying a modified BETA method as previously(83,95). We constructed a weighted cistrome-transcriptome score per peak binding site per gene per cell background (wt-C-T), and tested whether these values were significantly changed between ChromHMM states, treatments and cell backgrounds; all relationships are shown in Supplementary Figure 16B .…”

“…The AR and H3K27ac shared binding sites that were driven by RARg were more frequently annotated to Enza-regulated genes (Supplementary Figure 16A), and justified using a weighted cistrome-transcriptome approach (wt-C-T) (11,61,67) to measure how RARg-dependent AR cistromes significantly impacted the regulation of DHT and Enza-regulated genes (Supplementary Figure 16B). This revealed that RARg-TACC1 significantly increased the strength of the relationship between AR binding in Active Enhancers or Promoters and both basal and regulated gene expression (Figure 7A).…”

“…Differential expression analyses between upper quartile RARG and lower quartile ONECUT2, and vice versa, identified DEGs, which significantly related to high neuroendocrine score tumors (X 2 =8.5; pval = 0.003) (Figure 7D). We also measured how the RARg complex impacted AR gene regulation and in the SU2C cohort and discovered that several coregulators including SSRPI (68) and BAZ1A (67), significantly and positively impacted the strength of the correlations between AR expression and AR enhancer dependent target genes (Figure 7E). Finally, we tested if miR96 BR genes (n~660), and the RARg-TACC1 and ONECUT2 antagonized genes (termed RARgvsOC2; n~1400) were associated with PCa progression (69), metastasis (70), and alternative lineages (28).…”