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.
Authors
Yingai Jane Jin, Sally Wang, Joshua Cho, M. Angelica Selim, Tim Wright, George Mosialos, Jennifer Y. Zhang
(A) H&E staining of CyldEΔ9/Δ9 mice skin tissues treated with DMSO solvent or 10058-F4. Arrows mark sebaceous glands. Graph shows averages of sebaceous gland cells counted from 10 images of each condition. Data represent 25th–75th percentiles (box), median (line), and 5th and 95th percentiles (whiskers). (B–C) Immunostaining for cleaved caspase 3 and Ki-67 (orange); nuclei (blue, Hoechst 32558). Graphs show the average number of cells positively stained for cleaved caspase 3 and Ki-67 counted from 6 images of 2 different mice treated with the same condition. Data represent 25th–75th percentiles (box), median (line), and 5th and 95th percentiles (whiskers). P values were obtained via 2-tiered Student t test. (D) Immunoperoxidase staining of human cylindroma and sebaceous adenoma for phospho-c–Myc (S62) (brown) counterstained with hematoxylin. Two representative patient samples were shown for each group (n = 10). Scale bar: 100 μm.