Publication Date:
2011-03-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348545/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348545/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ceol, Craig J -- Houvras, Yariv -- Jane-Valbuena, Judit -- Bilodeau, Steve -- Orlando, David A -- Battisti, Valentine -- Fritsch, Lauriane -- Lin, William M -- Hollmann, Travis J -- Ferre, Fabrizio -- Bourque, Caitlin -- Burke, Christopher J -- Turner, Laura -- Uong, Audrey -- Johnson, Laura A -- Beroukhim, Rameen -- Mermel, Craig H -- Loda, Massimo -- Ait-Si-Ali, Slimane -- Garraway, Levi A -- Young, Richard A -- Zon, Leonard I -- CA103846/CA/NCI NIH HHS/ -- CA146455/CA/NCI NIH HHS/ -- DK055381/DK/NIDDK NIH HHS/ -- HG002668/HG/NHGRI NIH HHS/ -- K08 DK075432/DK/NIDDK NIH HHS/ -- K08 DK075432-04/DK/NIDDK NIH HHS/ -- K08DK075432-04/DK/NIDDK NIH HHS/ -- K99AR056899-02/AR/NIAMS NIH HHS/ -- R00 AR056899/AR/NIAMS NIH HHS/ -- R00 AR056899-02/AR/NIAMS NIH HHS/ -- R01 CA103846/CA/NCI NIH HHS/ -- R01 CA103846-09/CA/NCI NIH HHS/ -- R01 CA146445/CA/NCI NIH HHS/ -- R01 CA146445-03/CA/NCI NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- R01 HG002668-08/HG/NHGRI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 24;471(7339):513-7. doi: 10.1038/nature09806.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430779" target="_blank"〉PubMed〈/a〉
Keywords:
Age of Onset
;
Amino Acid Substitution
;
Animals
;
Animals, Genetically Modified
;
Cell Transformation, Neoplastic/genetics
;
Chromatin Immunoprecipitation
;
Chromosomes, Human, Pair 1/genetics
;
DNA Copy Number Variations/*genetics
;
Disease Models, Animal
;
Gene Amplification/*genetics
;
Gene Expression Profiling
;
Gene Expression Regulation, Neoplastic/genetics
;
Genes, Homeobox/genetics
;
Histone-Lysine N-Methyltransferase/*genetics/metabolism
;
Humans
;
Melanocytes/cytology/enzymology/metabolism/pathology
;
Melanoma/enzymology/*genetics/*pathology
;
Nevus/enzymology
;
Oncogenes/genetics
;
Protein Methyltransferases/*genetics/*metabolism
;
Proto-Oncogene Proteins B-raf/chemistry/genetics/metabolism
;
Zebrafish/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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