Increased Susceptibility to Skin Carcinogenesis Associated with a Spontaneous Mouse Mutation in the Palmitoyl Transferase Zdhhc13 Gene

• DOI: 10.1038/jid.2015.314
• Publication Date: 2015-08-19T13:55:35Z
• Authors: Carlos J. Perez; Lars Mecklenburg; Jean Jaubert; Lucia Martinez-Sa...; Brian M. Iritani; Alexsandra Espejo; Eleonora Napoli; Gyu Song; Marcela del Río; John DiGiovanni; Cecilia Giulivi; Mark T. Bedford; Sharon Y.R. Dent; Richard D. Wood; Donna F. Kusewitt; Jean-Louis Guénet; Claudio J. Conti; Fernando Benavides
• Keywords: Keratinocytes; 0301 basic medicine; Skin Neoplasms; Clinical sciences; MESH: Codon, Terminator; MESH: Epidermal Cells; Biochemistry; MESH: Acyltransferases / genetics*; MESH: Keratinocytes / physiology; Mice; 2.1 Biological and endogenous factors; MESH: Animals; Aetiology; Cancer; Skin; NF-kappa B; 3. Good health; Phenotype; Neutrophil Infiltration; Codon, Terminator; Stem Cell Research - Nonembryonic - Non-Human; Oncology and Carcinogenesis; Clinical Sciences; Dermatology; MESH: Phenotype; MESH: Skin Neoplasms / etiology; MESH: Skin Neoplasms / genetics*; Article; 03 medical and health sciences; MESH: Genetic Predisposition to Disease*; Genetics; Animals; Genetic Predisposition to Disease; Terminator; MESH: NF-kappa B / physiology; Codon; MESH: Mice; Molecular Biology; Biomedical and Clinical Sciences; Dermatology & Venereal Diseases; MESH: Leukocyte Elastase / metabolism; Cell Biology; MESH: Bromodeoxyuridine / metabolism; Stem Cell Research; MESH: Neutrophil Infiltration; [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics; Bromodeoxyuridine; Epidermal Cells; Mutation; MESH: Mutation*; NIH 3T3 Cells; Leukocyte Elastase; Acyltransferases; MESH: NIH 3T3 Cells

Here we describe a spontaneous mutation in the Zdhhc13 (zinc finger, DHHC domain containing 13) gene (also called Hip14l), one of 24 genes encoding palmitoyl acyltransferase (PAT) enzymes in the mouse. This mutation (Zdhhc13luc) was identified as a nonsense base substitution, which results in a premature stop codon that generates a truncated form of the ZDHHC13 protein, representing a potential loss-of-function allele. Homozygous Zdhhc13luc/Zdhhc13luc mice developed generalized hypotrichosis, associated with abnormal hair cycle, epidermal and sebaceous gland hyperplasia, hyperkeratosis, and increased epidermal thickness. Increased keratinocyte proliferation and accelerated transit from basal to more differentiated layers were observed in mutant compared with wild-type (WT) epidermis in untreated skin and after short-term 12-O-tetradecanoyl-phorbol-13-acetate treatment and acute UVB exposure. Interestingly, this epidermal phenotype was associated with constitutive activation of NF-κB (RelA) and increased neutrophil recruitment and elastase activity. Furthermore, tumor multiplicity and malignant progression of papillomas after chemical skin carcinogenesis were significantly higher in mutant mice than WT littermates. To our knowledge, this is the first report of a protective role for PAT in skin carcinogenesis.