The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset
Open accessAbstract
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.
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The methyltransferase complex containing SETDB1 and SUV39H1 represses developmental genes such as Hox genes, accelerating melanoma.
“Another study suggests that the methyltransferase complex containing SETDB1 and SUV39H1 represses developmental genes, such as Hox genes, resulting in alterations of gene expression that accelerate melanoma10.”
From Multi-omics analysis identifies glioblastoma dependency on H3K9me3 methyltransferase activity (2025) · cites this paper as [10]
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- Authors
- Ceol, C. J., Houvras, Y., Jane-Valbuena, J., Bilodeau, S., Orlando, D. A., Battisti, V., Fritsch, L., Lin, W. M., Hollmann, T. J., Ferré, F., Bourque, C., Burke, C. J., Turner, L., Uong, A., Johnson, L. A., Beroukhim, R., Mermel, C. H., Loda, M., Ait-Si-Ali, S., Garraway, L. A., Young, R. A., & Zon, L. I.
- Affiliations
- Boston Children's Hospital (US)
- Whitehead Institute for Biomedical Research (US)
- Centre National de la Recherche Scientifique (FR)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Zon, Leonard I.
- ORCID
- Venue
- Nature
- Published
- 2011-03
- Volume
- 471
- Issue
- 7339
- Pages
- 513-517
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3348545
- OpenAlex
- W2074329146
- Cited by
- 542
- References
- 23
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 16 · 2023: 24 · 2022: 42 · 2021: 36 · 2020: 51 · 2019: 46 · 2018: 34 · 2017: 41 · 2016: 49 · 2015: 39 · 2014: 36 · 2013: 40 · 2012: 37
- FWCI
- 17.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Canadian Institutes of Health Research
- National Human Genome Research Institute (HG002668, R01HG002668)
- National Cancer Institute (R01CA103846, CA103846, CA146455, R01CA146445)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK053298, DK055381, K08DK075432)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K99AR056899, R00AR056899)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- SETDB1, histone methyltransferase, melanoma, BRAF V600E mutation, oncogene cooperation, zebrafish melanoma model, gene amplification, chromosome 1, neural crest differentiation, leflunomide, neural crest stem cells, Hox genes, H3K9 methylation, BRAF inhibitors, anticancer drug development, copy number variation
- MeSH terms
- Histone Methyltransferases, Animals, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 1, Disease Models, Animal, Gene Amplification, Genes, Homeobox, Humans, Melanocytes, Melanoma, Nevus, Oncogenes, Histone-Lysine N-Methyltransferase, Protein Methyltransferases, Zebrafish, Gene Expression Regulation, Neoplastic, Age of Onset, Amino Acid Substitution, Gene Expression Profiling, Animals, Genetically Modified, Chromatin Immunoprecipitation, Proto-Oncogene Proteins B-raf, DNA Copy Number Variations
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