Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma.
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.
Massoumi
Ramin
R
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Kuphal
Silke
S
Hellerbrand
Claus
C
Haas
Bodo
B
Wild
Peter
P
Spruss
Thilo
T
Pfeifer
Alexander
A
Fässler
Reinhard
R
Bosserhoff
Anja K
AK
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; C530104:CCND1 protein, human; D015820:Cadherins; D011518:Proto-Oncogene Proteins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD