Abstract 3619: Vitamin D receptor function in African American prostate cancer is disrupted by reduced BAZ1A/SMARCA5
Authors: Hussain Shahid , Siddappa Manjunath , Wani Sajad A. , Jafari Hedieh , Gray Jaimie S. , Wu Hsu-Chang , Tang Hancong , Long Mark D. , Elhussin Isra , Karanam Balasubramanyam , Wang Honghe , Morgan Rebecca , Hardiman Gary , Adelani Isaacson B. , Oladapo Rotimi , Murphy Adam R. , Marshall James R. , Halbert Chanita Highes , Sucheston-Campbell Lara E. , Yates Clayton , Campbell Moray J. 
Published: June 2022

Abstract
The biological drivers of prostate cancer (PCa) health disparities remain enigmatic. There are genomic differences, for example in the incidence of TMPRSS2 and ERG gene fusions which differ between European American (EA) and African American (AA) PCa. Accumulating epidemiological evidence suggests loss of vitamin D receptor VDR signaling contributes to AA PCa. Therefore, we investigated the VDR signaling in AA and EA prostate models. VDR protein levels were comparable between AA (RC43N, RC43T, RC77N, RC77T) and EA cells (HPr1AR, LNCaP) but RIME analyses identified significant AA-EA differences in VDR binding of coactivators (e.g. NCOA5), corepressors (e.g. HDAC2), and components of SWI/SNF and circadian rhythm complexes. ATAC-Seq identified 1α,25(OH)2D3-stimulated gain in nucleosome free (NF) regions was greatest in RC43N (non-malignant AA cells) and enriched for circadian rhythm transcription motifs (e.g. CLOCK). In RC43T AA PCa cells 1α,25(OH)2D3 led to a loss of NF free regions. Similarly, VDR ChIP-Seq revealed the cistrome was greater in AA cell models, and was dynamically altered in RC43N cells by 1α,25(OH)2D3 and overlapped with the SWI/SNF component SMARCA4, but 1α,25(OH)2D3 led to reduced VDR binding in RC43T cells. The 1α,25(OH)2D3-regulated transcriptome was largest in RC43N and RC43T but GSEA terms were frequently and oppositely enriched, for example Reactome S phase genes were negatively enriched in RC43N, but positively enriched in RC43T. Cistrome-transcriptome integration identified the most significant relationships between VDR binding and the magnitude of 1α,25(OH)2D3-regulated genes in RC43N. Global coregulator analyses identified significantly reduced BAZ1A/SMARCA5 in AA PCa in TCGA and a published cohort of ~1500 AA/EA tumors. Restoring BAZ1A expression in cells resulted in significantly enhanced 1α,25(OH)2D3-regulated transcriptome in RC43N and RC43T cells, and hypergeometric tests revealed the significant enrichment of direct VDR target genes. The footprint of altered AA VDR signaling was evident in three previously established clinical cohorts. Serum miRNA that predicted AA progression from HGPIN to PCa were enriched for 1α,25(OH)2D3-regulated VDR targets; AA tumors from a vitaminD3-treated chemotherapy trail were enriched for VDR-bound genes; and, tumors from men with low serum 25(OH)D3 levels were significantly enriched for VDR target genes identified in AA but not EA PCa. Together, these data suggest VDR transcriptional control is most potent and dynamic in AA prostate cells, and is primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmental-regulated serum vitamin D3 levels most acutely suppress these actions in AA PCa. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes that contributes to PCa health disparities.
Citation Format: Shahid Hussain, Manjunath Siddappa, Sajad A. Wani, Hedieh Jafari, Jaimie S. Gray, Hsu-Chang Wu, Hancong Tang, Mark D. Long, Isra Elhussin, Balasubramanyam Karanam, Honghe Wang, Rebecca Morgan, Gary Hardiman, Isaacson B. Adelani, Rotimi Oladapo, Adam R. Murphy, James R. Marshall, Chanita Highes Halbert, Lara E. Sucheston-Campbell, Clayton Yates, Moray J. Campbell. Vitamin D receptor function in African American prostate cancer is disrupted by reduced BAZ1A/SMARCA5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3619.