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


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.

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Figure 1: SETDB1 accelerates melanoma formation in zebrafish.
Figure 2: Effects of SETDB1 on melanoma cells and melanocytes.
Figure 3: SETDB1 target gene regulation and histone methyltransferase complex formation.
Figure 4: High level expression of SETDB1 protein is common in human melanomas but not naevi or normal melanocytes.

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Gene Expression Omnibus

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The data discussed in this publication have been deposited in the NCBI Gene Expression Omnibus database under accession number GSE26372.


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We thank D. Harrington, R. White and Y. Zhou for discussions; C. Lawrence, I. Adatto and L.-K. Zhang for expert fish care; G. Frampton for bioinformatics assistance; and K. Kwan, C.-B. Chien, and J. Boehm for reagents. This work was supported by grants from the Damon Runyon Cancer Research Foundation (C.J.C., DRG-1855-05), the Charles A. King Trust Foundation (C.J.C.), a Young Investigator Award from the American Society of Clinical Oncology (Y.H.), the Canadian Institutes of Health Research (S.B.) and the National Institutes of Health (C.J.C., K99AR056899-02; Y.H., K08DK075432-04; R.A.Y., CA146455, HG002668; and L.I.Z., CA103846 and DK055381).

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Authors and Affiliations



C.J.C. and Y.H. contributed equally to this work and are listed alphabetically. C.J.C., Y.H. and L.I.Z. conceived the project, designed and analysed the experiments, and wrote the manuscript. C.J.C. and Y.H. performed the zebrafish experiments and contributed to the other experiments. J.J.-V. performed the tissue culture experiments. S.B. performed the ChIP-seq experiments and analysed the data. V.B., L.F., S.A.-S.-A. performed the biochemistry studies on SETDB1. L.A.J. performed the fluorescence in situ hybridization studies. T.J.H. performed the immunohistochemistry experiments. W.M.L., R.B. and C.H.M. analysed the copy number data. D.A.O. analysed the SETDB1-overexpression microarray data for WM451Lu cells. F.F. designed a database to manage and analyse tumour incidence data. C.B., C.J.B., L.T. and A.U. provided technical assistance. M.L., L.A.G. and R.A.Y. provided input into the preparation of the manuscript.

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Correspondence to Leonard I. Zon.

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Competing interests

L.I.Z. is a founder and stockholder of Fate Therapeutics and a scientific adviser for Stemgent.

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Supplementary Information

This file contains Supplementary Figures 1-18 with legends and 2 additional references. (PDF 14772 kb)

Supplementary Tables

This file contains Supplementary Tables 1-5 (Table 1 pp 1-406, Table 2 pp 407-896, Table 3 pp 897-923, Table 4 pg 924 and Table 5 pp 925-926). (PDF 24070 kb)

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Ceol, C., Houvras, Y., Jane-Valbuena, J. et al. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature 471, 513–517 (2011).

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