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Vitamin D₃ is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D₃ deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling pathways, essential to maintaining non-malignancy, may provide additional drug targets to mitigate disparate outcomes for men with PCa, especially AA men. We conducted RNA sequencing on an AA non-malignant prostate cell line, RC-77N/E, comparing untreated cells to those treated with 10 nM of vitamin D₃ metabolite, 1α,25(OH)₂D₃, at 24 h. Differential gene expression analysis revealed 1601 significant genes affected by 1α,25(OH)₂D₃ treatment. Pathway enrichment analysis predicted 1α,25(OH)₂D_3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways (<i>p</i> < 0.05). Prioritizing genes with vitamin D response elements and associating expression levels with overall survival (OS) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) cohort, we identified <i>ANLN</i> (Anillin) and <i>ECT2</i> (Epithelial Cell Transforming 2) as potential prognostic PCa biomarkers. Both genes were strongly correlated and significantly downregulated by 1α,25(OH)₂D₃ treatment, where low expression was statistically associated with better overall survival outcomes in the TCGA PRAD public cohort. Increased <i>ANLN</i> and <i>ECT2</i> mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort (<i>p</i> < 0.05) and an AA non-malignant/tumor-matched cohort. Our findings suggest 1α,25(OH)₂D₃ regulation of these biomarkers may be significant for PCa prevention. In addition, 1α,25(OH)₂D₃ could be used as an adjuvant treatment targeting actin cytoskeleton signaling and actin cytoskeleton-related signaling pathways, particularly among AA men.