The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset
Oncogenes BRAF(V600E) and SETDB1 in melanoma Transgenic zebrafish carrying the human oncogene BRAF(V600E) , the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of canc...
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| Veröffentlicht in: | Nature (London) 2011-03, Vol.471 (7339), p.513-517 |
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| creator | Ceol, Craig J. Houvras, Yariv Jane-Valbuena, Judit Bilodeau, Steve Orlando, David A. Battisti, Valentine Fritsch, Lauriane Lin, William M. Hollmann, Travis J. Ferré, Fabrizio Bourque, Caitlin Burke, Christopher J. Turner, Laura Uong, Audrey Johnson, Laura A. Beroukhim, Rameen Mermel, Craig H. Loda, Massimo Ait-Si-Ali, Slimane Garraway, Levi A. Young, Richard A. Zon, Leonard I. |
| description | Oncogenes
BRAF(V600E)
and
SETDB1
in melanoma
Transgenic zebrafish carrying the human oncogene
BRAF(V600E)
, the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of cancer genetics and in drug development. Ceol
et al
. screen for genes that cooperate with mutated
BRAF
, and identify
SETDB1
as capable of accelerating melanoma formation in fish. The gene is found in a region that is frequently amplified in human melanomas, and its gene product, SETDB1, is a histone methylating enzyme that is often overexpressed in those melanomas. This work establishes
SETDB1
as an important oncogene. White
et al
. find expression of a gene signature in melanoma-susceptible zebrafish embryos that is indicative of disrupted differentiation of neural crest progenitors. A chemical screen identifies leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, as an inhibitor of neural crest stem cells. Leflunomide has antimelanoma activity in human melanoma xenografts and might prove useful as an anticancer drug, particularly in combination with BRAF inhibitors.
Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of
HOX
genes.
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
1
,
2
.
BRAF(V600E)
mutations are also present in benign melanocytic naevi
3
, 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
4
,
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), w |
| doi_str_mv | 10.1038/nature09806 |
| format | Article |
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BRAF(V600E)
and
SETDB1
in melanoma
Transgenic zebrafish carrying the human oncogene
BRAF(V600E)
, the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of cancer genetics and in drug development. Ceol
et al
. screen for genes that cooperate with mutated
BRAF
, and identify
SETDB1
as capable of accelerating melanoma formation in fish. The gene is found in a region that is frequently amplified in human melanomas, and its gene product, SETDB1, is a histone methylating enzyme that is often overexpressed in those melanomas. This work establishes
SETDB1
as an important oncogene. White
et al
. find expression of a gene signature in melanoma-susceptible zebrafish embryos that is indicative of disrupted differentiation of neural crest progenitors. A chemical screen identifies leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, as an inhibitor of neural crest stem cells. Leflunomide has antimelanoma activity in human melanoma xenografts and might prove useful as an anticancer drug, particularly in combination with BRAF inhibitors.
Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of
HOX
genes.
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
1
,
2
.
BRAF(V600E)
mutations are also present in benign melanocytic naevi
3
, 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
4
,
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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature09806</identifier><identifier>PMID: 21430779</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>692/420/2489/68 ; 692/699/67/1813/1634 ; Age of Onset ; Amino Acid Substitution ; Animals ; Animals, Genetically Modified ; Biological and medical sciences ; Cancer ; Cell Transformation, Neoplastic - genetics ; Chromatin Immunoprecipitation ; Chromosomes, Human, Pair 1 - genetics ; Danio rerio ; Dermatology ; Development and progression ; Disease Models, Animal ; DNA Copy Number Variations - genetics ; Gene Amplification - genetics ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - genetics ; Genes, Homeobox - genetics ; Genetic aspects ; Genetics ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase - genetics ; Histone-Lysine N-Methyltransferase - metabolism ; Humanities and Social Sciences ; Humans ; letter ; Life Sciences ; Medical sciences ; Melanocytes - cytology ; Melanocytes - enzymology ; Melanocytes - metabolism ; Melanocytes - pathology ; Melanoma ; Melanoma - enzymology ; Melanoma - genetics ; Melanoma - pathology ; Methyltransferases ; multidisciplinary ; Mutation ; Nevus - enzymology ; Oncogenes - genetics ; Physiological aspects ; Protein Methyltransferases - genetics ; Protein Methyltransferases - metabolism ; Proteins ; Proto-Oncogene Proteins B-raf - chemistry ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins B-raf - metabolism ; Risk factors ; Science ; Science (multidisciplinary) ; Zebrafish - genetics</subject><ispartof>Nature (London), 2011-03, Vol.471 (7339), p.513-517</ispartof><rights>Springer Nature Limited 2011</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2011 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Mar 24, 2011</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c753t-30f68b6fdf5c3d22acab8a43a4bf8313ff32a663914923892212f51726588d233</citedby><cites>FETCH-LOGICAL-c753t-30f68b6fdf5c3d22acab8a43a4bf8313ff32a663914923892212f51726588d233</cites><orcidid>0000-0003-3041-7141 ; 0000-0002-7754-9486</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature09806$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature09806$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23947206$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21430779$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03051695$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Ceol, Craig J.</creatorcontrib><creatorcontrib>Houvras, Yariv</creatorcontrib><creatorcontrib>Jane-Valbuena, Judit</creatorcontrib><creatorcontrib>Bilodeau, Steve</creatorcontrib><creatorcontrib>Orlando, David A.</creatorcontrib><creatorcontrib>Battisti, Valentine</creatorcontrib><creatorcontrib>Fritsch, Lauriane</creatorcontrib><creatorcontrib>Lin, William M.</creatorcontrib><creatorcontrib>Hollmann, Travis J.</creatorcontrib><creatorcontrib>Ferré, Fabrizio</creatorcontrib><creatorcontrib>Bourque, Caitlin</creatorcontrib><creatorcontrib>Burke, Christopher J.</creatorcontrib><creatorcontrib>Turner, Laura</creatorcontrib><creatorcontrib>Uong, Audrey</creatorcontrib><creatorcontrib>Johnson, Laura A.</creatorcontrib><creatorcontrib>Beroukhim, Rameen</creatorcontrib><creatorcontrib>Mermel, Craig H.</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><creatorcontrib>Ait-Si-Ali, Slimane</creatorcontrib><creatorcontrib>Garraway, Levi A.</creatorcontrib><creatorcontrib>Young, Richard A.</creatorcontrib><creatorcontrib>Zon, Leonard I.</creatorcontrib><title>The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Oncogenes
BRAF(V600E)
and
SETDB1
in melanoma
Transgenic zebrafish carrying the human oncogene
BRAF(V600E)
, the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of cancer genetics and in drug development. Ceol
et al
. screen for genes that cooperate with mutated
BRAF
, and identify
SETDB1
as capable of accelerating melanoma formation in fish. The gene is found in a region that is frequently amplified in human melanomas, and its gene product, SETDB1, is a histone methylating enzyme that is often overexpressed in those melanomas. This work establishes
SETDB1
as an important oncogene. White
et al
. find expression of a gene signature in melanoma-susceptible zebrafish embryos that is indicative of disrupted differentiation of neural crest progenitors. A chemical screen identifies leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, as an inhibitor of neural crest stem cells. Leflunomide has antimelanoma activity in human melanoma xenografts and might prove useful as an anticancer drug, particularly in combination with BRAF inhibitors.
Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of
HOX
genes.
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
1
,
2
.
BRAF(V600E)
mutations are also present in benign melanocytic naevi
3
, 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
4
,
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.</description><subject>692/420/2489/68</subject><subject>692/699/67/1813/1634</subject><subject>Age of Onset</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Chromatin Immunoprecipitation</subject><subject>Chromosomes, Human, Pair 1 - genetics</subject><subject>Danio rerio</subject><subject>Dermatology</subject><subject>Development and progression</subject><subject>Disease Models, Animal</subject><subject>DNA Copy Number Variations - genetics</subject><subject>Gene Amplification - genetics</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Genes, Homeobox - genetics</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>Histone Methyltransferases</subject><subject>Histone-Lysine N-Methyltransferase - genetics</subject><subject>Histone-Lysine N-Methyltransferase - metabolism</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>letter</subject><subject>Life Sciences</subject><subject>Medical sciences</subject><subject>Melanocytes - cytology</subject><subject>Melanocytes - enzymology</subject><subject>Melanocytes - metabolism</subject><subject>Melanocytes - pathology</subject><subject>Melanoma</subject><subject>Melanoma - enzymology</subject><subject>Melanoma - genetics</subject><subject>Melanoma - pathology</subject><subject>Methyltransferases</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Nevus - enzymology</subject><subject>Oncogenes - genetics</subject><subject>Physiological aspects</subject><subject>Protein Methyltransferases - genetics</subject><subject>Protein Methyltransferases - metabolism</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins B-raf - chemistry</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Proto-Oncogene Proteins B-raf - metabolism</subject><subject>Risk factors</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Zebrafish - genetics</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp10s1v0zAUAPAIgVgZnLijaBNCE2T4K45zLGWwSRVIrIij5TrPrafE6WwH0f8el5ZtRUU5RHJ-7znvI8teYnSOERXvnYqDB1QLxB9lI8wqXjAuqsfZCCEiCiQoP8qehXCDECpxxZ5mRwQziqqqHmV6toR8aUPsHeQdxOW6jV65YMCrAPn1xezjB5zbkHvQg_fgYrvOVbdqrbHQ5NaloFa5vlO5ck2utIY2hUYIuY0h712A-Dx7YlQb4MXufZx9_3Qxm1wW06-frybjaaGrksaCIsPFnJvGlJo2hCit5kIxqtjcCIqpMZQozmmNWU2oqAnBxKSCCC-FaAilx9nZNu9StXLlbaf8WvbKysvxVG7OEE0N4HX5Eyf7ZmtXvr8dIETZ2ZD-PdUC_RBkjQhlggie5Mk_8qYfvEuFSFHWhNGSbNKdbtFCtSCtM33qot6klGNS0nQvZ1VSxQG1AJc61qYBGJuO9_zJAa9X9lY-ROcHUHoa6Kw-mPVsLyCZCL_iQg0hyKvrb_v27f_tePZj8uWg1r4PwYO5mwJGcrOr8sGuJv1q19hh3kFzZ_8uZwKvd0AFrVqT9lLbcO9ozSryJ9G7rQvpk1uAv5_QoXt_Ay1W-ns</recordid><startdate>20110324</startdate><enddate>20110324</enddate><creator>Ceol, 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histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset</title><author>Ceol, Craig J. ; Houvras, Yariv ; Jane-Valbuena, Judit ; Bilodeau, Steve ; Orlando, David A. ; Battisti, Valentine ; Fritsch, Lauriane ; Lin, William M. ; Hollmann, Travis J. ; Ferré, Fabrizio ; Bourque, Caitlin ; Burke, Christopher J. ; Turner, Laura ; Uong, Audrey ; Johnson, Laura A. ; Beroukhim, Rameen ; Mermel, Craig H. ; Loda, Massimo ; Ait-Si-Ali, Slimane ; Garraway, Levi A. ; Young, Richard A. ; Zon, Leonard I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c753t-30f68b6fdf5c3d22acab8a43a4bf8313ff32a663914923892212f51726588d233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>692/420/2489/68</topic><topic>692/699/67/1813/1634</topic><topic>Age of Onset</topic><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Chromatin Immunoprecipitation</topic><topic>Chromosomes, Human, Pair 1 - genetics</topic><topic>Danio rerio</topic><topic>Dermatology</topic><topic>Development and progression</topic><topic>Disease Models, Animal</topic><topic>DNA Copy Number Variations - genetics</topic><topic>Gene Amplification - genetics</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic - genetics</topic><topic>Genes, Homeobox - genetics</topic><topic>Genetic aspects</topic><topic>Genetics</topic><topic>Histone Methyltransferases</topic><topic>Histone-Lysine N-Methyltransferase - genetics</topic><topic>Histone-Lysine N-Methyltransferase - metabolism</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>letter</topic><topic>Life Sciences</topic><topic>Medical sciences</topic><topic>Melanocytes - cytology</topic><topic>Melanocytes - enzymology</topic><topic>Melanocytes - metabolism</topic><topic>Melanocytes - pathology</topic><topic>Melanoma</topic><topic>Melanoma - enzymology</topic><topic>Melanoma - genetics</topic><topic>Melanoma - pathology</topic><topic>Methyltransferases</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Nevus - enzymology</topic><topic>Oncogenes - genetics</topic><topic>Physiological aspects</topic><topic>Protein Methyltransferases - genetics</topic><topic>Protein Methyltransferases - metabolism</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins B-raf - chemistry</topic><topic>Proto-Oncogene Proteins B-raf - genetics</topic><topic>Proto-Oncogene Proteins B-raf - metabolism</topic><topic>Risk factors</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Zebrafish - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ceol, Craig J.</creatorcontrib><creatorcontrib>Houvras, Yariv</creatorcontrib><creatorcontrib>Jane-Valbuena, Judit</creatorcontrib><creatorcontrib>Bilodeau, Steve</creatorcontrib><creatorcontrib>Orlando, David A.</creatorcontrib><creatorcontrib>Battisti, Valentine</creatorcontrib><creatorcontrib>Fritsch, Lauriane</creatorcontrib><creatorcontrib>Lin, William M.</creatorcontrib><creatorcontrib>Hollmann, Travis J.</creatorcontrib><creatorcontrib>Ferré, Fabrizio</creatorcontrib><creatorcontrib>Bourque, Caitlin</creatorcontrib><creatorcontrib>Burke, Christopher J.</creatorcontrib><creatorcontrib>Turner, Laura</creatorcontrib><creatorcontrib>Uong, Audrey</creatorcontrib><creatorcontrib>Johnson, Laura A.</creatorcontrib><creatorcontrib>Beroukhim, Rameen</creatorcontrib><creatorcontrib>Mermel, Craig H.</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><creatorcontrib>Ait-Si-Ali, Slimane</creatorcontrib><creatorcontrib>Garraway, Levi A.</creatorcontrib><creatorcontrib>Young, Richard A.</creatorcontrib><creatorcontrib>Zon, Leonard I.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Middle School</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech 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Database</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ceol, Craig J.</au><au>Houvras, Yariv</au><au>Jane-Valbuena, Judit</au><au>Bilodeau, Steve</au><au>Orlando, David A.</au><au>Battisti, Valentine</au><au>Fritsch, Lauriane</au><au>Lin, William M.</au><au>Hollmann, Travis J.</au><au>Ferré, Fabrizio</au><au>Bourque, Caitlin</au><au>Burke, Christopher J.</au><au>Turner, Laura</au><au>Uong, Audrey</au><au>Johnson, Laura A.</au><au>Beroukhim, Rameen</au><au>Mermel, Craig H.</au><au>Loda, Massimo</au><au>Ait-Si-Ali, Slimane</au><au>Garraway, Levi A.</au><au>Young, Richard A.</au><au>Zon, Leonard I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2011-03-24</date><risdate>2011</risdate><volume>471</volume><issue>7339</issue><spage>513</spage><epage>517</epage><pages>513-517</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Oncogenes
BRAF(V600E)
and
SETDB1
in melanoma
Transgenic zebrafish carrying the human oncogene
BRAF(V600E)
, the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of cancer genetics and in drug development. Ceol
et al
. screen for genes that cooperate with mutated
BRAF
, and identify
SETDB1
as capable of accelerating melanoma formation in fish. The gene is found in a region that is frequently amplified in human melanomas, and its gene product, SETDB1, is a histone methylating enzyme that is often overexpressed in those melanomas. This work establishes
SETDB1
as an important oncogene. White
et al
. find expression of a gene signature in melanoma-susceptible zebrafish embryos that is indicative of disrupted differentiation of neural crest progenitors. A chemical screen identifies leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, as an inhibitor of neural crest stem cells. Leflunomide has antimelanoma activity in human melanoma xenografts and might prove useful as an anticancer drug, particularly in combination with BRAF inhibitors.
Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of
HOX
genes.
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
1
,
2
.
BRAF(V600E)
mutations are also present in benign melanocytic naevi
3
, 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
4
,
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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>21430779</pmid><doi>10.1038/nature09806</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0003-3041-7141</orcidid><orcidid>https://orcid.org/0000-0002-7754-9486</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2011-03, Vol.471 (7339), p.513-517 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_03051695v1 |
| source | MEDLINE; Springer Online Journals Complete; Nature Journals Online |
| subjects | 692/420/2489/68 692/699/67/1813/1634 Age of Onset Amino Acid Substitution Animals Animals, Genetically Modified Biological and medical sciences Cancer Cell Transformation, Neoplastic - genetics Chromatin Immunoprecipitation Chromosomes, Human, Pair 1 - genetics Danio rerio Dermatology Development and progression Disease Models, Animal DNA Copy Number Variations - genetics Gene Amplification - genetics Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - genetics Genes, Homeobox - genetics Genetic aspects Genetics Histone Methyltransferases Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Humanities and Social Sciences Humans letter Life Sciences Medical sciences Melanocytes - cytology Melanocytes - enzymology Melanocytes - metabolism Melanocytes - pathology Melanoma Melanoma - enzymology Melanoma - genetics Melanoma - pathology Methyltransferases multidisciplinary Mutation Nevus - enzymology Oncogenes - genetics Physiological aspects Protein Methyltransferases - genetics Protein Methyltransferases - metabolism Proteins Proto-Oncogene Proteins B-raf - chemistry Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Risk factors Science Science (multidisciplinary) Zebrafish - genetics |
| title | The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T04%3A16%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20histone%20methyltransferase%20SETDB1%20is%20recurrently%20amplified%20in%20melanoma%20and%20accelerates%20its%20onset&rft.jtitle=Nature%20(London)&rft.au=Ceol,%20Craig%20J.&rft.date=2011-03-24&rft.volume=471&rft.issue=7339&rft.spage=513&rft.epage=517&rft.pages=513-517&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature09806&rft_dat=%3Cgale_hal_p%3EA253305647%3C/gale_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=859243521&rft_id=info:pmid/21430779&rft_galeid=A253305647&rfr_iscdi=true |