1?, 25-Dihydroxyvitamin D? and the vitamin D receptor regulates ?Np63? levels and keratinocyte proliferation.

ABSTRACT: 1?, 25-dihydroxyvitamin D3 (VD3), a secosteriod that has been explored as an anti-cancer agent, was also shown to promote cell survival. Its receptor, the Vitamin D Receptor (VDR), is a direct target of the proto-oncogene ?Np63?, which is overexpressed in non-melanoma skin cancers. The interconnection between VDR/VD3 signaling and ?Np63?, led us to examine whether VDR/VD3 signaling promotes keratinocyte proliferation by regulating ?Np63? levels. Our data demonstrate that VDR regulates ?Np63? expression at both the transcript and protein level. Interestingly, although low doses of VD3 led to an increase in ?Np63? protein levels and keratinocyte proliferation, high doses of VD3 failed to increase ?Np63? protein levels and resulted in reduced proliferation. Increased expression of ?Np63? by low dose VD3 was shown to be dependent on VDR and critical for the proliferative effects of VD3. VD3-mediated increases in ?Np63? protein levels occur via activation of both p38 MAPK and Akt kinases. Finally, analysis of samples from patients with squamous cell carcinoma (SCC), basal cell carcinoma and precursors to invasive SCC demonstrated a significant correlation between p63 and VDR levels when compared with healthy normal skin control samples. Delineation of the mechanisms by which VD3 exerts its effect on ?Np63? and cell proliferation is critical for determining the future of VD3 in cancer therapies.

SUBMITTER: Hill NT 

PROVIDER: S-EPMC4669830 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature