CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.
CYLD has been recognized as a tumor suppressor due to its dominant genetic linkage to multiple types of epidermal tumors and a range of other cancers. The molecular mechanisms governing CYLD control of skin cancer are still unclear. Here, we showed that K14-driven epidermal expression of a patient-relevant and catalytically ... deficient CYLD truncated mutant (CYLD(m)) sensitized mice to skin tumor development in response to 7,12-dimethylbenz[α]anthracene (DMBA)/(12-O-tetradecanoylphorbol-13-acetate) TPA challenge. Tumors developed on transgenic mice were prone to malignant progression and lymph node metastasis and displayed increased activation of c-Jun-NH2-kinase (JNK) and the downstream c-Jun and c-Fos proteins. Most importantly, topical application of a pharmacologic JNK inhibitor significantly reduced tumor development and abolished metastasis in the transgenic mice. Further in line with these animal data, exogenous expression of CYLD(m) in A431, a human squamous cell carcinoma (SCC) cell line, markedly enhanced cell growth, migration, and subcutaneous tumor growth in an AP1-depdendent manner. In contrast, expression of the wild-type CYLD inhibited SCC tumorigenesis and AP1 function. Most importantly, CYLD(m) not only increased JNK activation but also induced an upregulation of K63 ubiquitination on both c-Jun and c-Fos, leading to sustained AP1 activation. Our findings uncovered c-Jun and c-Fos as novel CYLD targets and underscore that CYLD controls epidermal tumorigenesis through blocking the JNK/AP1 signaling pathway at multiple levels.
Mesh Terms:
9,10-Dimethyl-1,2-benzanthracene, Animals, Carcinogens, Carcinoma, Squamous Cell, Cysteine Endopeptidases, Disease Progression, Epidermis, Humans, Hyperplasia, Immunoblotting, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Lymphatic Metastasis, Mice, Mice, Transgenic, Mutation, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Skin Neoplasms, Tetradecanoylphorbol Acetate, Transcription Factor AP-1, Tumor Cells, Cultured, Tumor Suppressor Proteins, Ubiquitination
9,10-Dimethyl-1,2-benzanthracene, Animals, Carcinogens, Carcinoma, Squamous Cell, Cysteine Endopeptidases, Disease Progression, Epidermis, Humans, Hyperplasia, Immunoblotting, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Lymphatic Metastasis, Mice, Mice, Transgenic, Mutation, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Skin Neoplasms, Tetradecanoylphorbol Acetate, Transcription Factor AP-1, Tumor Cells, Cultured, Tumor Suppressor Proteins, Ubiquitination
Cancer Prev Res (Phila)
Date: Jun. 01, 2011
PubMed ID: 21478324
View in: Pubmed Google Scholar
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