MON-271 Vitamin D Receptor with Calcium Sensing Receptor Control Epidermal Tumorigenesis Through Oxidative Stress And DNA Repair Genes With Tumor Suppressor P53 Signaling

Abstract Disclosure: M.B. Meyer: None. I. Yeh: None. Z. Lin: None. C.T. Wong: None. D.H. Oh: None. D.D. Bikle: None. The vitamin D receptor (VDR) with calcium sensing receptor (CASR) regulates epidermal proliferation and differentiation. Deletion of both Vdr and Casr genes from Krt14 expressing epidermal keratinocyte (conditional double knockout, cDKO) causes alopecia and delays wound re-epithelialization. Furthermore, we found that cDKO spontaneously generates squamous cell carcinoma (SCC) in the skin after aging (> 8 months). Here, we investigated the causative molecular mechanism for Vdr/Casr to prevent epidermal tumorigenesis. Genome wide expression profiling and bioinformatic analyses indicted that Vdr/Casr regulate oxidative stress responses through the p53 signaling pathway in epidermal keratinocytes in newborn and younger mice (< 3 months). Indeed, cDKO keratinocytes decrease the expression of genes involved in oxidative stress and DNA repair responses. Vdr deletion sustains both basic and UVB induced reactive oxygen species and delays the clearance of UV-induced pyrimidine (6-4) pyrimidone photoproducts in cultured keratinocytes. We also analyzed individual transcriptional adaptations of epidermal keratinocytes in cDKO mice at the single-cell level (scRNA-seq and with spatial transcriptomics using the in situ Xenium platform). Vdr/Casr deletion prevents normal proliferation and differentiation but generates a unique cell population expressing SCC markers in young mice, implicating early predisposition to malignant transformation towards SCC. Chip-seq studies on human keratinocytes showed that VDR is colocalized with UVB induced P53 peaks in the regulatory region of FOS, XPC, CDKN1A (p21) and other P53 target genes essential to prevent epidermal tumorigenesis, parallel to their increased expression by UVB. Moreover, their expression is reduced in cDKO skin in vivo. These results suggest that Vdr/Casr has anti-tumor activity in the epidermis, by enhancing protection of the skin against DNA damage and oxidative stress in part through VDR epigenetic crosstalk with P53 signaling. Presentation: Monday, July 14, 2025