The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset.
Nature, 2011/3/24;471(7339):513-7.
Ceol CJ[1], Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferré F, Bourque C, Burke CJ, Turner L, Uong A, Johnson LA, Beroukhim R, Mermel CH, Loda M, Ait-Si-Ali S, Garraway LA, Young RA, Zon LI
Affiliations
PMID: 21430779DOI: 10.1038/nature09806
Impact factor: 69.504
Abstract
The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.
MeSH terms
Age of Onset; Amino Acid Substitution; Animals; Animals, Genetically Modified; Cell Transformation, Neoplastic; Chromatin Immunoprecipitation; Chromosomes, Human, Pair 1; DNA Copy Number Variations; Disease Models, Animal; Gene Amplification; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, Homeobox; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Melanocytes; Melanoma; Nevus; Oncogenes; Protein Methyltransferases; Proto-Oncogene Proteins B-raf; Zebrafish
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