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

Craig J. Ceol; Yariv Houvras; Judit Jane-Valbuena; Steve Bilodeau; David A. Orlando; Valentine Battisti; Lauriane Fritsch; William M. Lin; Travis J. Hollmann; Fabrizio Ferré; Caitlin Bourque; Christopher J. Burke; Laura Turner; Audrey Uong; Laura A. Johnson; Rameen Beroukhim; Craig H. Mermel; Massimo Loda; Slimane Ait-Si-Ali; Levi A. Garraway; Richard A. Young; Leonard I. Zon

doi:10.1038/nature09806

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

Craig J. Ceol, Yariv Houvras, Judit Jane-Valbuena, Steve Bilodeau, David A. Orlando, Valentine Battisti, Lauriane Fritsch, William M. Lin, Travis J. Hollmann, Fabrizio Ferré, Caitlin Bourque, Christopher J. Burke, Laura Turner, Audrey Uong, Laura A. Johnson, Rameen Beroukhim, Craig H. Mermel, Massimo Loda, Slimane Ait-Si-Ali, Levi A. GarrawayRichard A. Young, Leonard I. Zon

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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 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.

Original language	English (US)
Pages (from-to)	513-518
Number of pages	6
Journal	Nature
Volume	471
Issue number	7339
DOIs	https://doi.org/10.1038/nature09806
State	Published - Mar 24 2011
Externally published	Yes

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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., ... Zon, L. I. (2011). The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature, 471(7339), 513-518. https://doi.org/10.1038/nature09806

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 2011, 'The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset', Nature, vol. 471, no. 7339, pp. 513-518. https://doi.org/10.1038/nature09806

@article{4bc8f71ae4ce4bdea532241dedde7b87,

title = "The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset",

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 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.",

author = "Ceol, {Craig J.} and Yariv Houvras and Judit Jane-Valbuena and Steve Bilodeau and Orlando, {David A.} and Valentine Battisti and Lauriane Fritsch and Lin, {William M.} and Hollmann, {Travis J.} and Fabrizio Ferr{\'e} and Caitlin Bourque and Burke, {Christopher J.} and Laura Turner and Audrey Uong and Johnson, {Laura A.} and Rameen Beroukhim and Mermel, {Craig H.} and Massimo Loda and Slimane Ait-Si-Ali and Garraway, {Levi A.} and Young, {Richard A.} and Zon, {Leonard I.}",

note = "Funding Information: 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).",

year = "2011",

month = mar,

day = "24",

doi = "10.1038/nature09806",

language = "English (US)",

volume = "471",

pages = "513--518",

journal = "Nature",

issn = "0028-0836",

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number = "7339",

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TY - JOUR

T1 - The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset

AU - Ceol, Craig J.

AU - Houvras, Yariv

AU - Jane-Valbuena, Judit

AU - Bilodeau, Steve

AU - Orlando, David A.

AU - Battisti, Valentine

AU - Fritsch, Lauriane

AU - Lin, William M.

AU - Hollmann, Travis J.

AU - Ferré, Fabrizio

AU - Bourque, Caitlin

AU - Burke, Christopher J.

AU - Turner, Laura

AU - Uong, Audrey

AU - Johnson, Laura A.

AU - Beroukhim, Rameen

AU - Mermel, Craig H.

AU - Loda, Massimo

AU - Ait-Si-Ali, Slimane

AU - Garraway, Levi A.

AU - Young, Richard A.

AU - Zon, Leonard I.

N1 - Funding Information: 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).

PY - 2011/3/24

Y1 - 2011/3/24

N2 - 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.

AB - 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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ER -

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

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