The role of histone demethylase UTX on epidermal homeostasis and carcinogenesis

Histone modifiers are among the most highly mutated genes in all forms of cancer, with histone demethylase UTX (KDM6A) being one of the most frequent. Found on the X chromosome, UTX is one of the few genes to escape X inactivation and functions as a major enhancer regulator. UTX establishes the active enhancer landscape through its histone demethylase activity as well as its ability to complex with other activating histone modifiers. UTX is implicated in many epithelial cancers and is commonly mutated or lost in cutaneous squamous cell carcinoma (cSCC). This is supported by loss of UTX expression in cSCC upon immunohistochemical staining. UTY, the Y-linked paralog of UTX, retains minimal catalytic function but can potentially compensate for UTX loss by other mechanisms. This may account for some of the sex specific differences that have been observed in the risk and severity of cSCC, given that mutations in UTX are typically heterozygous. Despite its demonstrated role in tumor suppression across cancers, there is virtually no understanding of how it functions during epidermal homeostasis or carcinogenesis. To address these questions, we generated mice with epidermal deletions of Utx. Intriguingly, we observed that homozygous Utx knockout female mice show regions of epidermal hyperplasia, an expanded keratin 14 basal layer and increased immune invasion in the skin when compared to controls. In contrast, male mice missing their one copy of Utx, as well as heterozygous female mice lacking only one copy of Utx, appear phenotypically normal. At the transcriptional level, we find that depletion of UTX leads to numerous alterations in the expression of both immune and metabolic genes, consistent with a recent discovery that UTX senses cellular oxygen. Taken together, these data offer new insights into how UTX may be critical for maintaining epidermal homeostasis and proper gene expression, and how when lost, UTX depletion may lead to increased cancer risk.