The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset
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Open Access
- 23 March 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 471 (7339), 513-517
- https://doi.org/10.1038/nature09806
Abstract
Transgenic zebrafish carrying the human oncogene BRAF(V600E), the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of cancer genetics and in drug development. Ceol et al. screen for genes that cooperate with mutated BRAF, and identify SETDB1 as capable of accelerating melanoma formation in fish. The gene is found in a region that is frequently amplified in human melanomas, and its gene product, SETDB1, is a histone methylating enzyme that is often overexpressed in those melanomas. This work establishes SETDB1 as an important oncogene. White et al. find expression of a gene signature in melanoma-susceptible zebrafish embryos that is indicative of disrupted differentiation of neural crest progenitors. A chemical screen identifies leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, as an inhibitor of neural crest stem cells. Leflunomide has antimelanoma activity in human melanoma xenografts and might prove useful as an anticancer drug, particularly in combination with BRAF inhibitors. Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of HOX genes. 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 pathway1,2. BRAF(V600E) mutations are also present in benign melanocytic naevi3, 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 oncogenes4,5. 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.Keywords
This publication has 23 references indexed in Scilit:
- The landscape of somatic copy-number alteration across human cancersNature, 2010
- Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genesNature, 2010
- SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell stateJournal of Bone and Joint Surgery, 2009
- Somatic mutations of the histone H3K27 demethylase gene UTX in human cancerNature Genetics, 2009
- Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cellsDisease Models & Mechanisms, 2009
- Assessing the significance of chromosomal aberrations in cancer: Methodology and application to gliomaProceedings of the National Academy of Sciences of the United States of America, 2007
- The Tol2kit: A multisite gateway‐based construction kit for Tol2 transposon transgenesis constructsDevelopmental Dynamics, 2007
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003
- Mutations of the BRAF gene in human cancerNature, 2002