The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset.

TitleThe histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset.
Publication TypeJournal Article
Year of Publication2011
AuthorsCeol CJ, Houvras Y, Jané-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
JournalNature
Volume471
Issue7339
Pagination513-7
Date Published2011 Mar 24
ISSN1476-4687
KeywordsAge of Onset, Amino Acid Substitution, Animals, Animals, Genetically Modified, Cell Transformation, Neoplastic, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 1, Disease Models, Animal, DNA Copy Number Variations, 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
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.

DOI10.1038/nature09806
Alternate JournalNature
PubMed ID21430779
Grant ListK99AR056899-02 / AR / NIAMS NIH HHS / United States
CA146455 / CA / NCI NIH HHS / United States
CA103846 / CA / NCI NIH HHS / United States
K08DK075432-04 / DK / NIDDK NIH HHS / United States
/ CAPMC / CIHR / Canada
DK055381 / DK / NIDDK NIH HHS / United States
HG002668 / HG / NHGRI NIH HHS / United States
Related Faculty: 
Massimo Loda, M.D.

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