title: The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset.
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.
authors: Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Craig J
authors: CJ
authors: Ceol
authors: Yariv
authors: Y
authors: Houvras
authors: Judit
authors: J
authors: Jane-Valbuena
authors: Steve
authors: S
authors: Bilodeau
authors: David A
authors: DA
authors: Orlando
authors: Valentine
authors: V
authors: Battisti
authors: Lauriane
authors: L
authors: Fritsch
authors: William M
authors: WM
authors: Lin
authors: Travis J
authors: TJ
authors: Hollmann
authors: Fabrizio
authors: F
authors: Ferré
authors: Caitlin
authors: C
authors: Bourque
authors: Christopher J
authors: CJ
authors: Burke
authors: Laura
authors: L
authors: Turner
authors: Audrey
authors: A
authors: Uong
authors: Laura A
authors: LA
authors: Johnson
authors: Rameen
authors: R
authors: Beroukhim
authors: Craig H
authors: CH
authors: Mermel
authors: Massimo
authors: M
authors: Loda
authors: Slimane
authors: S
authors: Ait-Si-Ali
authors: Levi A
authors: LA
authors: Garraway
authors: Richard A
authors: RA
authors: Young
authors: Leonard I
authors: LI
authors: Zon
mesh_terms: D017668:Age of Onset; D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004195:Disease Models, Animal; D005784:Gene Amplification / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005801:Genes, Homeobox / Q000235:genetics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D009506:Nevus / Q000201:enzymology; D009857:Oncogenes / Q000235:genetics; D011496:Protein Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics
chemical_list: D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf