CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Miliani de Marval, P; Lutfeali, S; Jin, JY; Leshin, B; Selim, MA; Zhang, JY

Published Date

  • June 2011

Published In

Volume / Issue

  • 4 / 6

Start / End Page

  • 851 - 859

PubMed ID

  • 21478324

Pubmed Central ID

  • 21478324

Electronic International Standard Serial Number (EISSN)

  • 1940-6215

Digital Object Identifier (DOI)

  • 10.1158/1940-6207.CAPR-10-0360

Language

  • eng

Conference Location

  • United States