The chromatin remodeler SMARCA5 displays ancestry-specific functions in African American prostate cancer

Previously, we identified that BAZ1A and SMARCA5 were significantly downregulated in in African American (AA) prostate cancer (PCa), and that BAZ1A altered vitamin D receptor (VDR)-dependent transcriptional sensitivity. SMARCA5 is the ATPase core of different chromatin remodeling complexes, including WICH that promotes accessible chromatin at developmental enhancers, and NoRC, which mediated repression of rDNA transcription and contributes to nucleolar stress pathways. In the current study we tested how ancestry shaped the composition and impact of the SMARCA5 complex. Integrative ATAC-Seq, and H3K27ac and AR CUT&RUN in AA (RC43T and RC77T) and European American (EA, LNCaP) PCa cell models revealed AA-specific H3K27ac marked accessible chromatin. These regions were enriched for motifs including the basic leucine zipper/AP-1 motifs such as BATF and significantly intersected AA PCa enhancer landscapes. Likewise, the AR cistrome from AA PCa cell lines significantly intersected with the AR cistrome derived from AA primary tumors. To test whether SMARCA5 complex composition and function differed by ancestry, we performed CRISPR activation of SMARCA5 in AA and EA PCa models. RIME revealed selective assembly of SMARCA5 with WICH and NoRC subunits in AA, but not in EA cells. CUT&RUN demonstrated that AA-enriched SMARCA5 complexes targeted distinct enhancers and promoters compared to LNCaP cells and mirrored the basal H3K27ac cistromes. Reflecting lineage- and stress response-specific roles the AA SMARCA5 cistrome was enriched BATF, VDR, and p53/p73 motifs. Transcriptomic analysis demonstrated that SMARCA5 activation induced a strong luminal differentiation program unique to AA PCa, supported by GSEA. SMARCA5 controlled VDR target genes in AA cells included VDR governed miRNA (e.g. miR-200c) that also related to differentiation. Integrated ATAC- and RNA-Seq analyses demonstrated that luminal genes were the dominant contributors to active enhancer-transcriptome correlations in AA PCa, confirmed using random forest approaches. Finally, ancestry-stratified clinical cohorts from Africa, AA, and EA PCa showed significant clinical associations between vitamin D levels, SMARCA5-dependent gene signatures and tumor grade. Together, these findings suggest that reduced SMARCA5 expression impacts both the availability of lineage-defining active enhancers and the establishment of heterochromatin boundaries, potentially in response to stress (and mediated by p53/p73 pathways). In this manner, ancestry selectively disrupts the SMARCA5 complex, and shapes transcriptional outputs. SMARCA5 complex composition and its chromatin outputs represent ancestry-stratified features with potential biomarker and therapeutic relevance in AA PCa.