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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 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.

Pubmed ID: 21430779

Authors

  • Ceol CJ
  • Houvras Y
  • Jane-Valbuena J
  • Bilodeau S
  • Orlando DA
  • Battisti V
  • Fritsch L
  • Lin WM
  • Hollmann TJ
  • Ferré F
  • Bourque C
  • Burke CJ
  • Turner L
  • Uong A
  • Johnson LA
  • Beroukhim R
  • Mermel CH
  • Loda M
  • Ait-Si-Ali S
  • Garraway LA
  • Young RA
  • Zon LI

Journal

Nature

Publication Data

March 24, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: CA103846
  • Agency: NCI NIH HHS, Id: CA146455
  • Agency: NIDDK NIH HHS, Id: DK055381
  • Agency: NHGRI NIH HHS, Id: HG002668
  • Agency: NIDDK NIH HHS, Id: K08 DK075432
  • Agency: NIDDK NIH HHS, Id: K08 DK075432-04
  • Agency: NIDDK NIH HHS, Id: K08DK075432-04
  • Agency: NIAMS NIH HHS, Id: K99AR056899-02
  • Agency: NIAMS NIH HHS, Id: R00 AR056899
  • Agency: NIAMS NIH HHS, Id: R00 AR056899-02
  • Agency: NCI NIH HHS, Id: R01 CA103846
  • Agency: NCI NIH HHS, Id: R01 CA103846-09
  • Agency: NCI NIH HHS, Id: R01 CA146445
  • Agency: NCI NIH HHS, Id: R01 CA146445-03
  • Agency: NHGRI NIH HHS, Id: R01 HG002668
  • Agency: NHGRI NIH HHS, Id: R01 HG002668-08
  • Agency: NIGMS NIH HHS, Id: T32 GM007753
  • Agency: NHLBI NIH HHS, Id: T32 HL007627
  • Agency: Canadian Institutes of Health Research, Id:
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Age of Onset
  • Amino Acid Substitution
  • Animals
  • Animals, Genetically Modified
  • Cell Transformation, Neoplastic
  • Chromatin Immunoprecipitation
  • Chromosomes, Human, Pair 1
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Gene Amplification
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Homeobox
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Melanocytes
  • Melanoma
  • Nevus
  • Oncogenes
  • Protein Methyltransferases
  • Proto-Oncogene Proteins B-raf
  • Zebrafish