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Abstract:
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Objective: 1-alpha-25-dihydroxyvitamin D3 (VD3), explored as an anti-cancer agent, has recently been shown to also promote cell survival. VD3 exerts its effects via its cognate receptor; the Vitamin D Receptor (VDR). delta-Np63alpha, a proto-oncogene up-regulated in non-melanoma skin cancers, positively regulates VDR expression and is critical for VDR mediated development. The objective of this study was to determine if VDR/VD3 signaling promotes keratinocyte proliferation via regulation of delta-Np63alpha. Results and Conclusions: Loss of VDR leads to decreased delta-Np63alpha expression indicating that VDR transcriptionally regulates delta- Np63alpha. Interestingly, while low dose of VD3 led to increased deltaNp63alpha protein expression and keratinocyte proliferation, high doses of VD3 decreased deltaNp63alpha and reduced keratinocyte proliferation. The stabilization of delta-Np63alpha by VD3 was shown to be at the protein level, and critical to the pro-proliferative effects of VD3. Loss of VDR led to a dramatic reduction in both basal as well as VD3 induced cell proliferation. Immunofluorescence staining of delta-Np63alpha and VDR after VD3 treatment further confirmed an increase in delta-Np63alpha expression with low dose VD3 and a decrease expression of delta- Np63alpha with high dose VD3. Significance: We have demonstrated a dose dependent effect of VD3 on delta-Np63alphalevels. The effects of VD3 on delta-Np63alpha were shown to be VDR dependent and critical for keratinocyte proliferation. This study provides mechanistic insight into how VD3 can exert both pro- proliferative and pro-apoptotic effects via regulation of delta-Np63alpha levels. Delineation of the mechanisms by which VD3 exerts its effect on delta-Np63alpha will be critical for determining the future of VD3 in cancer therapies. |
