The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma
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[subscript 1, 2]. BRAF(V600E) mutations are also present in benign melanocytic naevi3, highlighting the importance of addit...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2012
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| Online Access: | http://hdl.handle.net/1721.1/75295 |
| _version_ | 1826210609529618432 |
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| author | Ceol, Craig J. Houvras, Yariv Jane-Valbuena, Judit Bilodeau, Steve Orlando, David A. Battisti, Valentine Fritsch, Lauriane Lin, William M. Hollmann, Travis J. Ferre, 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. |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Ceol, Craig J. Houvras, Yariv Jane-Valbuena, Judit Bilodeau, Steve Orlando, David A. Battisti, Valentine Fritsch, Lauriane Lin, William M. Hollmann, Travis J. Ferre, 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 | Ceol, Craig J. |
| collection | MIT |
| description | 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[subscript 1, 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 oncogenes[subscript 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. |
| first_indexed | 2024-09-23T14:52:21Z |
| format | Article |
| id | mit-1721.1/75295 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:52:21Z |
| publishDate | 2012 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/752952024-06-28T13:31:24Z The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset Ceol, Craig J. Houvras, Yariv Jane-Valbuena, Judit Bilodeau, Steve Orlando, David A. Battisti, Valentine Fritsch, Lauriane Lin, William M. Hollmann, Travis J. Ferre, 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. Whitehead Institute for Biomedical Research Mermel, Craig H. 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[subscript 1, 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 oncogenes[subscript 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. 2012-12-07T17:56:33Z 2012-12-07T17:56:33Z 2011-03 2010-08 Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/75295 Ceol, Craig J. et al. “The Histone Methyltransferase SETDB1 Is Recurrently Amplified in Melanoma and Accelerates Its Onset.” Nature 471.7339 (2011): 513–517. en_US http://dx.doi.org/10.1038/nature09806 Nature Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Ceol, Craig J. Houvras, Yariv Jane-Valbuena, Judit Bilodeau, Steve Orlando, David A. Battisti, Valentine Fritsch, Lauriane Lin, William M. Hollmann, Travis J. Ferre, 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. The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma |
| title | The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma |
| title_full | The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma |
| title_fullStr | The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma |
| title_full_unstemmed | The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma |
| title_short | The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma |
| title_sort | setdb1 histone methyltransferase is recurrently amplified in and accelerates melanoma |
| url | http://hdl.handle.net/1721.1/75295 |
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