Abstract
1α,25-Dihydroxyvitamin D3 signals via the vitamin D receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As patients with melanoma commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D-VDR signaling and replicated the findings in The Cancer Genome Atlas metastases. VDR expression was independently protective for melanoma-related death in both primary and metastatic disease. High tumor VDR expression was associated with upregulation of pathways mediating antitumor immunity and corresponding with higher imputed immune cell scores and histologically detected tumor-infiltrating lymphocytes. High VDR-expressing tumors had downregulation of proliferative pathways, notably Wnt/β-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases. Vitamin D deficiency (<25 nmol/L ∼ 10 ng/mL) shortened survival in primary melanoma in a VDR-dependent manner. In vitro functional validation studies showed that elevated vitamin D-VDR signaling inhibited Wnt/β-catenin signaling genes. Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail-vein metastasis assays. In summary, vitamin D-VDR signaling contributes to controlling pro-proliferative/immunosuppressive Wnt/β-catenin signaling in melanoma and this is associated with less metastatic disease and stronger host immune responses. This is evidence of a causal relationship between vitamin D-VDR signaling and melanoma survival, which should be explored as a therapeutic target in primary resistance to checkpoint blockade. SIGNIFICANCE: VDR expression could potentially be used as a biomarker to stratify patients with melanoma that may respond better to immunotherapy.
Highlights
1a,25-Dihydroxyvitamin D3 signals via the vitamin D receptor (VDR)
Low vitamin D levels are associated with thicker, poorerprognosis primary melanomas [11], and lower VDR expression is associated with melanoma progression [43, 44], but neither causality nor the mechanistic basis has been established
We demonstrate that vitamin D–VDR signaling is protective for melanoma-related death at least, in part, through inhibition of Wnt/b-catenin signaling, impacting on melanoma proliferation and antitumor immune response
Summary
1a,25-Dihydroxyvitamin D3 is the ligand for the dimeric vitamin D receptor (VDR) and retinoid X receptor (RXR): ligand–receptor binding facilitates transcription of target genes containing the vitamin D response element [1]. We have previously reported that higher serum vitamin D levels at recruitment were associated with lower American Joint Committee on Cancer (AJCC) stage and better melanoma-specific survival (MSS) in the Leeds Melanoma Cohort Vitamin D–VDR Signaling in Primary Melanoma Prognosis alteration (CNA) data were jointly analyzed to assess the pangenome effects of vitamin D–VDR signaling and to determine the processes most associated with this pathway. These findings were replicated in The Cancer Genome Atlas (TCGA) metastatic melanomas and functionally validated using in vitro and in vivo experiments
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
