摘要：SummaryVitamin D is an essential steroid hormone that regulates systemic calcium homeostasis and cell fate decisions. The prostate gland is hormonally regulated, requiring steroids for proliferation and differentiation of secretory luminal cells. Vitamin D deficiency is associated with an increased risk of lethal prostate cancer, which exhibits a dedifferentiated pathology, linking vitamin D sufficiency to epithelial differentiation. To determine vitamin D regulation of prostatic epithelial differentiation, patient-derived benign prostate epithelial organoids were grown in vitamin D-deficient or -sufficient conditions. Organoids were assessed by phenotype and single-cell RNA sequencing. Mechanistic validation demonstrated that vitamin D sufficiency promoted organoid growth and accelerated differentiation by inhibiting canonical Wnt activity and suppressing Wnt family member DKK3. Wnt and DKK3 were also reduced by vitamin D in prostate tissue explants by spatial transcriptomics. Wnt dysregulation is a known contributor to aggressive prostate cancer, thus findings further link vitamin D deficiency to lethal disease.Graphical abstractDisplay OmittedHighlights•Vitamin D sufficiency accelerates differentiation of patient-derived prostate organoids•Single-cell RNAseq of organoids reveals differentiation trajectory over time•Vitamin D inhibits canonical Wnt activity in human prostate organoids and explants•Inhibition of DKK3 by vitamin D promotes organoid growth and proliferationCell Biology; Developmental Biology; Transcriptomics
