The deubiquitinase-encoding gene Cyld displays a dominant genetic linkage to a 
wide spectrum of skin-appendage tumors, which could be collectively designated 
as CYLD mutant-syndrome (CYLDm-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 CYLDm through 
K14-Cre-mediated deletion of exon 9 (hereafter refer to CyldEΔ9/Δ9 ). CyldEΔ9/Δ9 
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 CYLDm-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 CyldEΔ9/Δ9 skin. Topical treatment with a pharmacological 
c-Myc inhibitor induced sebaceous and basal cell apoptosis in CyldEΔ9/Δ9 skin. 
Consistently, c-Myc activation was readily detected in human cylindroma and 
sebaceous adenoma. Taken together, our findings demonstrate that CyldEΔ9/Δ9 mice 
represent a disease-relevant animal model and identify TRAF6 and c-Myc as 
potential therapeutic targets for CYLDm-syndrome.