Dissection of an impact of VDR and RXRA on the genomic activity of 1,25(OH)2D3 in A431 squamous cell carcinoma

• DOI: 10.1016/j.mce.2023.112124
• Publication Date: 2023-12-19T04:26:13Z
• Authors: Anna M. Olszewska; Joanna I. Nowak; Kamil Myszczynski; Andrzej Słominski; Michał A. Żmijewski
• Keywords: Retinoid X receptor; A431 cells; CYP24A1

Human skin is the natural source, place of metabolism, and target for vitamin D3. The classical active form D3, 1,25(OH)2D3, expresses pluripotent properties intensively studied in cancer prevention therapy. To define specific role D3 receptor (VDR) its co-receptor retinoid X alpha (RXRA) genomic regulation, VDR or RXRA genes were silenced squamous cell carcinoma line A431 treated with 1,25(OH)2D3 at long incubation time points 24 h/72 h. Extending WT (wild-type) cells resulted a two-fold increase DEGs (differentially expressed genes) change amount downregulated from 37% to 53%. knockout led complete loss 1,25(OH)2D3-induced genome-wide gene regulation h point, but after 72 h, 20 found, which 75% downregulated, most them belonged ontology group "immune response". This may indicate existence an alternative, secondary response 1,25(OH)2D3. In contrast, treatment ΔRXRA only partially affected DEGs, suggesting RXRA-independent regulation. Interestingly, overexpression classic targets, like CYP24A1 (family subfamily A cytochrome P450 member 1) CAMP (cathelicidin antimicrobial peptide) was found be RXRA-independent. Also, immunofluorescence staining revealed partial VDR/RXRA colocalization treatment. Comparison transcriptome changes induced by normal keratinocytes vs. showed high type expression pattern few commonly regulated Activation pathway least reversed cancer-related genes, forming basis anti-cancer activates summary, independent activities suggest involvement alternative factors, opening new challenges this field.