title: CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.
abstract: 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.
authors.affiliation: Department of Dermatology, Duke University, Durham, North Carolina, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Miliani de Marval
authors.forename: Shazia
authors.initials: S
authors.lastname: Lutfeali
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Jin
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leshin
authors.forename: M Angelica
authors.initials: MA
authors.lastname: Selim
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Zhang
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D018450:Disease Progression; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008207:Lymphatic Metastasis; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002273:Carcinogens; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D048031:JNK Mitogen-Activated Protein Kinases; C409984:CYLD protein, human; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases; D013755:Tetradecanoylphorbol Acetate