Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness

Purpose: Dysregulated signaling of nuclear transcription factors vitamin D receptor (VDR) and Forkhead box M1 (FOXM1) plays important roles in transformation and tumorigenesis. In this study, we sought to determine whether VDR signaling causally affected FOXM1 signaling in and pathogenesis of pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Genetic and pharmacologic approaches were used to manipulate VDR signaling. The impacts of altered VDR signaling on FOXM1 expression and function in PDAC cells were determined using molecular and biochemical methods, whereas those on PDAC cell biology and tumorigenicity were determined using in vitro and in vivo experimental systems. The clinical relevance of our findings was validated by analyzing human PDAC specimens. Results: There was a striking inverse correlation between reduced expression of VDR and increased expression of FOXM1 in human PDAC cells and tissues. Treatment of PDAC cells with 1,25-dihydroxyvitamin D₃ (1,25D), its synthetic analogue EB1089 (EB), and VDR transgenics drastically inhibited FOXM1 signaling and markedly suppressed tumor stemness, growth, and metastasis. Mechanistically, 1,25D and EB repressed FOXM1 transcription and reduced the expression level of nuclear FOXM1 protein. Conclusion: Inactivation of Vitamin D/VDR signaling is a critical contributor to PDAC development and progression via elevated expression and function of FOXM1 and enhanced PDAC cell stemness, invasion, and metastasis.