Brenna Flowers, An Zhang, Weiwei Ma, Alexandra Zigrossi, Madeline Warrick, Jacob K Phillips, Mitchell F Denning, Maarten C Bosland, Li Liu, Alan M Diamond, Irida Kastrati
Selenoprotein F (SELENOF) is one of the 25 human selenoproteins that is highly sensitive to fluctuations in bioavailable selenium, an essential micronutrient. Although SELENOF has been implicated in cancer etiology, its precise role remains unclear. To define its contribution to carcinogenesis, Selenof knockout (KO) mice were exposed to the potent carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) and fed a high-fat, high-calorie Western diet. All Selenof KO mice developed tumors and did so more rapidly, whereas only 30% of wild-type mice developed tumors. This effect was further exacerbated by the Western diet regardless of Selenof status. Notably, the majority of DMBA-induced tumors in KO mice were skin lesions, predominantly cutaneous squamous cell carcinomas (SCCs) and benign papillomas. These tumors occurred at a four-fold higher frequency in KO mice than in wild-type controls, establishing SELENOF as a key tumor suppressor in the skin. To assess the relevance of these findings to human disease, we analyzed a skin cancer microarray containing patient samples of SCC, basal cell carcinoma, melanomas, and matched adjacent normal tissue. SELENOF expression was dramatically reduced across all tumor types relative to normal skin. Although the skin of Selenof KO mice appears histologically normal, transcriptomic profiling followed by enrichment analysis revealed significant downregulation of pathways related to epidermal development and keratinocyte differentiation as well as the upregulation of oxidative phosphorylation and mitochondrial metabolic pathways. Collectively, these findings support a causal link between SELENOF loss and skin cancer development and highlight a previously unrecognized role for SELENOF in safeguarding against skin carcinogenesis. Significance: Skin cancers are the most common human malignancies. SELENOF levels are significantly reduced in skin cancers, and experimental evidence establishes a critical tumor-suppressive role for SELENOF in the skin.