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

Abstract

The deubiquitinase-encoding gene <i>Cyld</i> displays a dominant genetic linkage to a wide spectrum of skin-appendage tumors, which could be collectively designated as CYLD mutant-syndrome (CYLD^m-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^m through K14-Cre-mediated deletion of exon 9 (hereafter refer to <i>Cyld^EΔ9/Δ9</i> ). <i>Cyld^EΔ9/Δ9</i> 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^m-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 <i>Cyld^EΔ9/Δ9</i> skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis in <i>Cyld^EΔ9/Δ9</i> skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate that <i>Cyld^EΔ9/Δ9</i> mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLD^m-syndrome.