Published online January 5, 2009
doi:10.1084/jem.20082044
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2009 Massoumi et al.
Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma
Ramin Massoumi1,6,
Silke Kuphal2,
Claus Hellerbrand3,
Bodo Haas5,
Peter Wild7,
Thilo Spruss4,
Alexander Pfeifer5,
Reinhard Fässler1, and
Anja K. Bosserhoff2
1 Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
2 Institute of Pathology, 3 Department of Internal Medicine I, 4 Institute of Pharmacy, University Regensburg, 93053 Regensburg, Germany
5 Institute for Pharmacology and Toxicology, University of Bonn, 53113 Bonn, Germany
6 Cell and Experimental Pathology, Department of Laboratory Medicine CRC, Malmö University Hospital, 205 02 Malmö, Sweden
7 Institute of Pathology, University Hospital Zürich, 8091 Zürich, Switzerland
CORRESPONDENCE Anja K. Bosserhoff:anja.bosserhoff{at}klinik.uni-regensburg.de
High malignancy and early metastasis are hallmarks of melanoma. Here, we report that the transcription factor Snail1 inhibits expression of the tumor suppressor CYLD in melanoma. As a direct consequence of CYLD repression, the protooncogene BCL-3 translocates into the nucleus and activates Cyclin D1 and N-cadherin promoters, resulting in proliferation and invasion of melanoma cells. Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo. Analysis of a tissue microarray with primary melanomas from patients revealed an inverse correlation of Snail1 induction and loss of CYLD expression. Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression. Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy.
Abbreviations used: asSnail, antisense Snail1; ChIP, chromatin immunoprecipitation; EMT, epithelial-mesenchymal transition; ERK, extracellular signal–regulated kinase; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; NHEM, normal human epidermal melanocyte;
© 2009 Massoumi et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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