166 Suppression of very long chain fatty acids as an early marker of skin carcinogenesis

Abstract

The role of very long chain fatty acids (VLCFAs) remains poorly understood in hyperplastic skin diseases like cancer. VLCFAs are carboxyl polymers of >20 chain saturated or unsaturated molecules. VLCFAs are elongated from smaller chain fatty acids by a family of elongases known as ELOVL. To study the potential role of VLCFAs in the genesis of skin cancer, we initially analyzed the transcriptome in experimental skin hyperplasia. The tumor promoter TPA (12-O-Tetradecanoylphorbol-13-Acetate) was applied to mutant p53 mouse skin for 7 days to induce a marked induction of S-phase keratinocytes (KCs) and hyperproliferation of the epidermis. Deletion of the mitotic Kinase AURORA-A (AUR-A) gene in TPA treated mutant p53 skin led to the accumulation of stalled KCs in the G2 and M phase of the cell cycle. RNA sequencing of AUR-A deleted skin revealed the downregulation of genes associated with VLCFA biology. To confirm the changes in VLCFA genes, we performed lipid composition analysis. Compared to WT skin, mutant p53 skin showed reduced levels of longer chain fatty acids (greater than C18 fatty acids). These changes were preserved in AUR-A deficient skin. Treatment of primary KCs or skin cancer cell lines with specific long chain fatty acids led to either cell death or cellular morphological changes that were dependent on the cell type. Lastly, meta-analysis of human and mouse published datasets of skin Squamous Cell Carcinomas (SCCs) versus normal skin revealed the downregulation of the VLCFA gene signature identified in our hyperplastic skin model. Our data strongly suggests that VLCFA suppression may be important in the progression of skin hyperplasia to carcinoma.