[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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

Subjects

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Primary accessions

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.

References

  1. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)

    Article  ADS  CAS  Google Scholar 

  2. Wan, P. T. et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF . Cell 116, 855–867 (2004)

    Article  CAS  Google Scholar 

  3. Pollock, P. M. et al. High frequency of BRAF mutations in nevi. Nature Genet. 33, 19–20 (2003)

    Article  CAS  Google Scholar 

  4. Curtin, J. A. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005)

    Article  CAS  Google Scholar 

  5. Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005)

    Article  ADS  CAS  Google Scholar 

  6. Lin, W. M. et al. Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res. 68, 664–673 (2008)

    Article  CAS  Google Scholar 

  7. Patton, E. E. et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr. Biol. 15, 249–254 (2005)

    Article  CAS  Google Scholar 

  8. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010)

    Article  ADS  CAS  Google Scholar 

  9. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005)

    Article  ADS  CAS  Google Scholar 

  10. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo . Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995)

    Article  ADS  CAS  Google Scholar 

  11. Santoriello, C. et al. Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells. Dis. Model. Mech. 2, 56–67 (2009)

    Article  CAS  Google Scholar 

  12. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    Article  ADS  CAS  Google Scholar 

  13. Mootha, V. K. et al. PGC-1α responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273 (2003)

    Article  ADS  CAS  Google Scholar 

  14. Bilodeau, S., Kagey, M. H., Frampton, G. M., Rahl, P. B. & Young, R. A. SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev. 23, 2484–2489 (2009)

    Article  CAS  Google Scholar 

  15. Wang, H. et al. mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Mol. Cell 12, 475–487 (2003)

    Article  CAS  Google Scholar 

  16. Fritsch, L. et al. A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol. Cell 37, 46–56 (2010)

    Article  ADS  CAS  Google Scholar 

  17. Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010)

    Article  ADS  CAS  Google Scholar 

  18. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet. 41, 521–523 (2009)

    Article  CAS  Google Scholar 

  19. Kwan, K. M. et al. The Tol2kit: a multisite gateway-based construction kit for Tol2 transposon transgenesis constructs. Dev. Dyn. 236, 3088–3099 (2007)

    Article  CAS  Google Scholar 

  20. Beroukhim, R. et al. Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc. Natl Acad. Sci. USA 104, 20007–20012 (2007)

    Article  ADS  CAS  Google Scholar 

  21. Nisolle, M. et al. Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone receptors A and B in leiomyomata and normal myometrium during the menstrual cycle and under gonadotrophin-releasing hormone agonist therapy. Hum. Reprod. 14, 2844–2850 (1999)

    Article  CAS  Google Scholar 

  22. Perner, S. et al. EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia 10, 298–302 (2008)

    Article  CAS  Google Scholar 

  23. Sarraf, S. A. & Stancheva, I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol. Cell 15, 595–605 (2004)

    Article  CAS  Google Scholar 

Download references

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).

Author information

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

Authors
  1. Craig J. Ceol
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yariv Houvras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Judit Jane-Valbuena
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steve Bilodeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David A. Orlando
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valentine Battisti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lauriane Fritsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William M. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Travis J. Hollmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fabrizio Ferré
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Caitlin Bourque
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christopher J. Burke
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Laura Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Audrey Uong
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Laura A. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Rameen Beroukhim
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Craig H. Mermel
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Massimo Loda
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Slimane Ait-Si-Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Levi A. Garraway
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Richard A. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Leonard I. Zon
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

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

Supplementary information

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)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09806

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer