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

Nature volume 471, pages 513–517 (2011)Cite this article

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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 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

Data deposits

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

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Acknowledgements

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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Author notes

  1. Craig J. Ceol & Yariv Houvras

    Present address: Present addresses: Program in Molecular Medicine, Program in Cell Dynamics, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. (C.J.C.); Departments of Surgery and Medicine, Weill Cornell Medical College and New York Presbyterian Hospital, New York, New York 10065, USA (Y.H.).,

  2. Craig J. Ceol and Yariv Houvras: These authors contributed equally to this work.

Authors and Affiliations

  1. Stem Cell Program and Hematology/Oncology, Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Craig J. Ceol, Yariv Houvras, Caitlin Bourque, Christopher J. Burke, Laura Turner, Audrey Uong & Leonard I. Zon

  2. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Yariv Houvras

  3. Departments of Medical Oncology, Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Judit Jane-Valbuena, William M. Lin, Laura A. Johnson, Rameen Beroukhim, Craig H. Mermel & Levi A. Garraway

  4. The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Judit Jane-Valbuena, William M. Lin, Laura A. Johnson, Rameen Beroukhim, Craig H. Mermel & Levi A. Garraway

  5. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Steve Bilodeau, David A. Orlando & Richard A. Young

  6. UMR7216 Epigénétique et Destin Cellulaire, CNRS, Université Paris-Diderot, 35 rue Hélène Brion, Paris, 75013, France

    Valentine Battisti, Lauriane Fritsch & Slimane Ait-Si-Ali

  7. Center for Molecular Oncologic Pathology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Travis J. Hollmann & Massimo Loda

  8. A. Rossi Fanelli Biochemical Sciences Department, Sapienza University of Rome, Rome 00185, Italy

    Fabrizio Ferré

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Contributions

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.

Corresponding author

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)

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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). https://doi.org/10.1038/nature09806

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