CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways.

Ke, Hengning

Augustine, Christina K

Gandham, Vineela D

Jin, Jane Y

Tyler, Douglas S

Akiyama, Steven K

Hall, Russell P

Zhang, Jennifer Y

United States

2017-08-02T14:13:39Z

2017-08-02T14:13:39Z

2013-01

The molecular mechanisms mediating cylindromatosis (CYLD) tumor suppressor function appear to be manifold. Here, we demonstrate that, in contrast to the increased levels of phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CYLD was decreased in a majority of the melanoma cell lines and tissues examined. Exogenous expression of CYLD but not its catalytically deficient mutant markedly inhibited melanoma cell proliferation and migration in vitro and subcutaneous tumor growth in vivo. In addition, the melanoma cells expressing exogenous CYLD were unable to form pulmonary tumor nodules following tail-vein injection. At the molecular level, CYLD decreased β1-integrin and inhibited pJNK induction by tumor necrosis factor-α or cell attachment to collagen IV. Moreover, CYLD induced an array of other molecular changes associated with modulation of the "malignant" phenotype, including a decreased expression of cyclin D1, N-cadherin, and nuclear Bcl3, and an increased expression of p53 and E-cadherin. Most interestingly, coexpression of the constitutively active MKK7 or c-Jun mutants with CYLD prevented the above molecular changes, and fully restored melanoma growth and metastatic potential in vivo. Our findings demonstrate that the JNK/activator protein 1 signaling pathway underlies the melanoma growth and metastasis that are associated with CYLD loss of function. Thus, restoration of CYLD and inhibition of JNK and β1-integrin function represent potential therapeutic strategies for treatment of malignant melanoma.

https://www.ncbi.nlm.nih.gov/pubmed/22832488

S0022-202X(15)35965-0

1523-1747

https://hdl.handle.net/10161/15169

eng

Elsevier BV

J Invest Dermatol

10.1038/jid.2012.253

Antigens, CD

Antigens, CD29

Cadherins

Cell Adhesion

Cell Line, Tumor

Cell Proliferation

Collagen Type IV

Cyclin D1

Disease Progression

Humans

MAP Kinase Kinase 7

MAP Kinase Signaling System

Melanoma

Mutation

Proto-Oncogene Proteins

Proto-Oncogene Proteins c-jun

Skin Neoplasms

Transcription Factor AP-1

Transcription Factors

Tumor Necrosis Factor-alpha

Tumor Suppressor Protein p53

Tumor Suppressor Proteins

CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways.

Journal article

Hall, Russell P|0000-0001-7621-4935

Zhang, Jennifer Y|0000-0002-4485-1750

https://www.ncbi.nlm.nih.gov/pubmed/22832488

221

229

1

Basic Science Departments

Clinical Science Departments

Dermatology

Duke

Duke Cancer Institute

Faculty

Immunology

Institutes and Centers

Pathology

School of Medicine

Published

133