1,25-Dihydroxyvitamin D3 Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line.

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)2D3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways (p < 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 ANLN (Anillin) and ECT2 (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 ANLN and ECT2 mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort (p < 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.

The complex interplay of modifiable risk factors affecting prostate cancer disparities in African American men.

Prostate cancer is the second most commonly diagnosed non-skin malignancy and the second leading cause of cancer death among men in the USA. However, the mortality rate of African American men aged 40-60 years is almost 2.5-fold greater than that of European American men. Despite screening and diagnostic and therapeutic advances, disparities in prostate cancer incidence and outcomes remain prevalent. The reasons that lead to this disparity in outcomes are complex and multifactorial. Established non-modifiable risk factors such as age and genetic predisposition contribute to this disparity; however, evidence suggests that modifiable risk factors (including social determinants of health, diet, steroid hormones, environment and lack of diversity in enrolment in clinical trials) are prominent contributing factors to the racial disparities observed. Disparities involved in the diagnosis, treatment and survival of African American men with prostate cancer have also been correlated with low socioeconomic status, education and lack of access to health care. The effects and complex interactions of prostate cancer modifiable risk factors are important considerations for mitigating the incidence and outcomes of this disease in African American men.