Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors.

The deubiquitinase-encoding gene displays a dominant genetic linkage to a wide spectrum of skin-appendage tumors, which could be collectively designated as CYLD mutant-syndrome (CYLD-syndrome). Despite recent advances, little is understood about the molecular mechanisms responsible for this painful and difficult-to-treat skin disease. Here, we generated a conditional mouse model with epidermis-targeted expression of a catalytically deficient CYLD through K14-Cre-mediated deletion of exon 9 (hereafter refer to ). mice were born alive but developed hair and sebaceous gland abnormalities and dental defects at 100% and 60% penetrance, respectively. Upon topical challenge with DMBA/TPA, these animals primarily developed sebaceous and basaloid tumors resembling human CYLD-syndrome as opposed to papilloma, which is most commonly induced in WT mice by this treatment. Molecular analysis revealed that TRAF6-K63-Ubiquitination (K63-Ub), c-Myc-K63-Ub, and phospho-c-Myc (S62) were markedly elevated in skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis in skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate that mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLD-syndrome.