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.
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.
Cancer research communications. 2023 Apr 18*** epublish ***
Manjunath Siddappa, Shahid Hussain, Sajad A Wani, Jason White, Hancong Tang, Jaimie S Gray, Hedieh Jafari, Hsu-Chang Wu, Mark D Long, Isra Elhussin, Balasubramanyam Karanam, Honghe Wang, Rebecca Morgan, Gary Hardiman, Isaacson B Adelani, Solomon O Rotimi, Adam R Murphy, Larisa Nonn, Melissa B Davis, Rick A Kittles, Chanita Hughes Halbert, Lara E Sucheston-Campbell, Clayton Yates, Moray J Campbell
Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio., Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, Alabama., Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York., School of Biological Sciences, Institute for Global Food Security, Queen's University Belfast, Belfast, United Kingdom., Department of Biochemistry, Covenant University, Ota, Ogun State, Nigeria., Department of Urology, Northwestern Medicine, Chicago, Illinois., Department of Pathology, University of Illinois at Chicago, Chicago, Illinois., Department of Surgery, Weill Cornell Medicine, New York City, New York., Division of Health Equities, Department of Population Sciences, City of Hope, Duarte, California., Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California., Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio.