Abstract 6346: The chromatin remodeler SMARCA5 selectively shapes nuclear receptor signaling in African American prostate cancer

Abstract SMARCA5 is found in distinct chromatin remodeling complexes where it regulates ATP hydrolysis to control nucleosome positioning required for gene expression and DNA repair. Previously, we established the chromatin remodeling enzyme SMARCA5 is significantly down-regulated in African American (AA) compared to European Americans (EA) prostate cancer (PCa). We have now explored how SMARCA5 distorts the epigenome and impacts transcription, as well as cell phenotypes. Firstly, we revealed that the H3K27ac cistrome had significantly different distributions between AA (RC43N) and EA (HPr1AR) normal cells, and AA (RC43T) and EA (LNCaP) PCa cells. Motif enrichment in H3K27ac revealed significant differences with Helix-Loop-Helix motifs enriched in RC43N compared to HPr1AR; and STAT motifs enriched in RC43T compared to LNCaP. Similarly, nuclear receptor (NR) motifs were distinct with vitamin D receptor (VDR) and orphan receptors (e.g., RORG) enriched in RC43T compared to LNCaP. Next we up-regulated SMARCA5’s using dCas9-VP64-activator in the same cells and tested the impact on gene expression with RNA-Seq following treatment with the VDR ligand (1, 25(OH)2D3, 100nM). SMARCA5 regulated ∼1200 genes in both RC43T and RC77T, and only ∼200 genes in LNCaP. The SMARCA5-dependent genes in AA PCa cells models were significantly enriched for luminal-differentiation genes. Likewise, in the AA compared to EA PCa models, GSEA analyses revealed enrichment for inflammation responses, and distinct NR signaling, such as progesterone signaling. Likewise LISA analyses revealed enrichment in the SMARCA5-dependent genes in AA PCa for progesterone signaling. Finally, we also identified a subset of miRNA related to differentiation that were uniquely regulated in AA PCa models by 1, 25(OH)2D3 and a significant number were also SMARCA5-dependent. Ongoing studies are addressing the effect of SMARCA5 on chromatin accessibility using ATAC-Seq. Overall, these studies support the concept the epigenome is shaped by genomic ancestry. The epigenomic-regulator SMARCA5 is significantly downregulated in AA PCa and impacts NRs, including VDR signaling. These findings suggest that African ancestry shapes SMARCA5 functions, NR signaling, and tumor outcomes. Citation Format: Shahid Hussain, Debasis Nayak, Sajad A. Wani, Isra Elhussin, Michael R. Freeman, Christopher C. Coss, Solomon O. Rotimi, Adam R. Murphy, Clayton Yates, Moray J. Campbell. The chromatin remodeler SMARCA5 selectively shapes nuclear receptor signaling in African American prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6346.