Transforming pathways unleashed by a HDAC2 mutation in human cancer
Although disruption of histone modification patterns is a common hallmark of human cancer, our knowledge of the mechanistic role of histone-modifying enzymes in its generation is very limited. We have recently identified an inactivating mutation in the histone deacetylase-2 (HDAC2) in sporadic carci...
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description | Although disruption of histone modification patterns is a common hallmark of human cancer, our knowledge of the mechanistic role of histone-modifying enzymes in its generation is very limited. We have recently identified an inactivating mutation in the histone deacetylase-2 (HDAC2) in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. Since HDAC2 seems to be a central player in epigenetic gene repression, we wondered whether HDAC2-truncating mutations conferred a particular expression signature on these cancer cells. Using unsupervised clustering analysis in microsatellite-unstable colorectal cancer cell lines, we have found that HDAC2 mutant cells (RKO and Co115) show a characteristically different expression microarray signature from HDAC2 wild-type cells (HCT-116, SW48, HCT-15 and LoVo). HDAC2 mutant cells exhibit upregulation of tumor-promoting genes, such as those of tyrosine kinases, mediators of cell cycle progression and angiogenic factors. The overexpression of these genes is associated with a loss of HDAC2 recruitment and a gain of histone H4 hyperacetylation in their particular 5′-end promoters, as observed by chromatin immunoprecipitation. Transfection of wild-type HDAC2 in mutant cells reverted this epigenetic pattern by repressing the transforming genes in association with HDAC2 promoter occupancy. These results suggest a role for HDAC2 mutations in human tumorigenesis through the derepression of key genes from multiple cellular transformation pathways. |
doi_str_mv | 10.1038/onc.2008.31 |
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We have recently identified an inactivating mutation in the histone deacetylase-2 (HDAC2) in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. Since HDAC2 seems to be a central player in epigenetic gene repression, we wondered whether HDAC2-truncating mutations conferred a particular expression signature on these cancer cells. Using unsupervised clustering analysis in microsatellite-unstable colorectal cancer cell lines, we have found that HDAC2 mutant cells (RKO and Co115) show a characteristically different expression microarray signature from HDAC2 wild-type cells (HCT-116, SW48, HCT-15 and LoVo). HDAC2 mutant cells exhibit upregulation of tumor-promoting genes, such as those of tyrosine kinases, mediators of cell cycle progression and angiogenic factors. The overexpression of these genes is associated with a loss of HDAC2 recruitment and a gain of histone H4 hyperacetylation in their particular 5′-end promoters, as observed by chromatin immunoprecipitation. Transfection of wild-type HDAC2 in mutant cells reverted this epigenetic pattern by repressing the transforming genes in association with HDAC2 promoter occupancy. These results suggest a role for HDAC2 mutations in human tumorigenesis through the derepression of key genes from multiple cellular transformation pathways.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2008.31</identifier><identifier>PMID: 18264134</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Angiogenesis ; Apoptosis ; Biological and medical sciences ; Cancer ; Carcinoma ; Care and treatment ; Cell Biology ; Cell cycle ; Cell Line, Tumor ; Cell physiology ; Cell transformation ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Chromatin ; Chromatin - metabolism ; Chromatin. Chromosome ; Cluster Analysis ; Colorectal cancer ; Colorectal carcinoma ; Derepression ; DNA microarrays ; Enzymes ; Epigenesis, Genetic ; Epigenetics ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Gene mutations ; Genetic aspects ; Genetics ; HDAC2 protein ; Health aspects ; Histone deacetylase ; Histone Deacetylase 2 ; Histone Deacetylases - genetics ; Histone Deacetylases - physiology ; Histone H4 ; Histones - metabolism ; Human Genetics ; Humans ; Immunoprecipitation ; Internal Medicine ; Kinases ; Medicine ; Medicine & Public Health ; Microsatellite instability ; Microsatellite Repeats ; Molecular and cellular biology ; Molecular genetics ; Mutants ; Mutation ; Neoplasms - metabolism ; Neovascularization, Pathologic ; Oncology ; Physiological aspects ; Promoter Regions, Genetic ; Repressor Proteins - genetics ; Repressor Proteins - physiology ; Risk factors ; short-communication ; Transcription Factors - metabolism ; Transfection ; Tumor cell lines ; Tumorigenesis ; Tyrosine</subject><ispartof>Oncogene, 2008-06, Vol.27 (28), p.4008-4012</ispartof><rights>Springer Nature Limited 2008</rights><rights>2008 INIST-CNRS</rights><rights>COPYRIGHT 2008 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jun 26, 2008</rights><rights>Nature Publishing Group 2008.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c503t-c27344f05558df6e803dbb2bb0b46aa92befd9d3567b6f260bb5cd454aa1bee33</citedby><cites>FETCH-LOGICAL-c503t-c27344f05558df6e803dbb2bb0b46aa92befd9d3567b6f260bb5cd454aa1bee33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2727,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20502032$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18264134$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ropero, S</creatorcontrib><creatorcontrib>Ballestar, E</creatorcontrib><creatorcontrib>Alaminos, M</creatorcontrib><creatorcontrib>Arango, D</creatorcontrib><creatorcontrib>Schwartz, S</creatorcontrib><creatorcontrib>Esteller, M</creatorcontrib><title>Transforming pathways unleashed by a HDAC2 mutation in human cancer</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Although disruption of histone modification patterns is a common hallmark of human cancer, our knowledge of the mechanistic role of histone-modifying enzymes in its generation is very limited. We have recently identified an inactivating mutation in the histone deacetylase-2 (HDAC2) in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. Since HDAC2 seems to be a central player in epigenetic gene repression, we wondered whether HDAC2-truncating mutations conferred a particular expression signature on these cancer cells. Using unsupervised clustering analysis in microsatellite-unstable colorectal cancer cell lines, we have found that HDAC2 mutant cells (RKO and Co115) show a characteristically different expression microarray signature from HDAC2 wild-type cells (HCT-116, SW48, HCT-15 and LoVo). HDAC2 mutant cells exhibit upregulation of tumor-promoting genes, such as those of tyrosine kinases, mediators of cell cycle progression and angiogenic factors. The overexpression of these genes is associated with a loss of HDAC2 recruitment and a gain of histone H4 hyperacetylation in their particular 5′-end promoters, as observed by chromatin immunoprecipitation. Transfection of wild-type HDAC2 in mutant cells reverted this epigenetic pattern by repressing the transforming genes in association with HDAC2 promoter occupancy. These results suggest a role for HDAC2 mutations in human tumorigenesis through the derepression of key genes from multiple cellular transformation pathways.</description><subject>Angiogenesis</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell physiology</subject><subject>Cell transformation</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Chromatin</subject><subject>Chromatin - metabolism</subject><subject>Chromatin. Chromosome</subject><subject>Cluster Analysis</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Derepression</subject><subject>DNA microarrays</subject><subject>Enzymes</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>HDAC2 protein</subject><subject>Health aspects</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase 2</subject><subject>Histone Deacetylases - genetics</subject><subject>Histone Deacetylases - physiology</subject><subject>Histone H4</subject><subject>Histones - metabolism</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Microsatellite instability</subject><subject>Microsatellite Repeats</subject><subject>Molecular and cellular biology</subject><subject>Molecular genetics</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Neoplasms - metabolism</subject><subject>Neovascularization, Pathologic</subject><subject>Oncology</subject><subject>Physiological aspects</subject><subject>Promoter Regions, Genetic</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - physiology</subject><subject>Risk factors</subject><subject>short-communication</subject><subject>Transcription Factors - metabolism</subject><subject>Transfection</subject><subject>Tumor cell lines</subject><subject>Tumorigenesis</subject><subject>Tyrosine</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqF0c9rFDEUB_AgFrtWT951UPSis778mh_HZa2tUPBSz-Elk-xOmcmsyQyy_70ZZ2lBKpJDIPkkLy9fQl5RWFPg1efBmzUDqNacPiErKsoil7IWT8kKagl5zTg7J89jvAOAsgb2jJzTihWCcrEi29uAProh9K3fZQcc97_wGLPJdxbj3jaZPmaYXX_ZbFnWTyOO7eCz1mf7qUefGfTGhhfkzGEX7cvTfEF-fL283V7nN9-vvm03N7mRwMfcsJIL4UBKWTWusBXwRmumNWhRINZMW9fUDZdFqQvHCtBamkZIgUi1tZxfkA_LvYcw_JxsHFXfRmO7Dr0dpqgY5RRoRf8PoeZQyTLBd3_Bu2EKPjWh_nxQVYpyrvv2nyr1JDkrWULrBe2ws6r1bhgDmjQa27dm8Na1aX1D65SBKGiRDnxcDpgwxBisU4fQ9hiOioKag1UpWDUHq_jc0uvTGybd2-bBnpJM4P0JYDTYuRSraeO9YyCBAZ_f-WlxMW35nQ0PzTxe983CPY5TsPf3JTOTJH4DIl3BnQ</recordid><startdate>20080626</startdate><enddate>20080626</enddate><creator>Ropero, S</creator><creator>Ballestar, E</creator><creator>Alaminos, M</creator><creator>Arango, D</creator><creator>Schwartz, S</creator><creator>Esteller, M</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20080626</creationdate><title>Transforming pathways unleashed by a HDAC2 mutation in human cancer</title><author>Ropero, S ; Ballestar, E ; Alaminos, M ; Arango, D ; Schwartz, S ; Esteller, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c503t-c27344f05558df6e803dbb2bb0b46aa92befd9d3567b6f260bb5cd454aa1bee33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Angiogenesis</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Carcinoma</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell physiology</topic><topic>Cell transformation</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Chromatin</topic><topic>Chromatin - metabolism</topic><topic>Chromatin. Chromosome</topic><topic>Cluster Analysis</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Derepression</topic><topic>DNA microarrays</topic><topic>Enzymes</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Fundamental and applied biological sciences. 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genetics</topic><topic>Repressor Proteins - physiology</topic><topic>Risk factors</topic><topic>short-communication</topic><topic>Transcription Factors - metabolism</topic><topic>Transfection</topic><topic>Tumor cell lines</topic><topic>Tumorigenesis</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ropero, S</creatorcontrib><creatorcontrib>Ballestar, E</creatorcontrib><creatorcontrib>Alaminos, M</creatorcontrib><creatorcontrib>Arango, D</creatorcontrib><creatorcontrib>Schwartz, S</creatorcontrib><creatorcontrib>Esteller, M</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>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</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>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</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 Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ropero, S</au><au>Ballestar, E</au><au>Alaminos, M</au><au>Arango, D</au><au>Schwartz, S</au><au>Esteller, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transforming pathways unleashed by a HDAC2 mutation in human cancer</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2008-06-26</date><risdate>2008</risdate><volume>27</volume><issue>28</issue><spage>4008</spage><epage>4012</epage><pages>4008-4012</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Although disruption of histone modification patterns is a common hallmark of human cancer, our knowledge of the mechanistic role of histone-modifying enzymes in its generation is very limited. 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subjects | Angiogenesis Apoptosis Biological and medical sciences Cancer Carcinoma Care and treatment Cell Biology Cell cycle Cell Line, Tumor Cell physiology Cell transformation Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Chromatin Chromatin - metabolism Chromatin. Chromosome Cluster Analysis Colorectal cancer Colorectal carcinoma Derepression DNA microarrays Enzymes Epigenesis, Genetic Epigenetics Fundamental and applied biological sciences. Psychology Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Gene mutations Genetic aspects Genetics HDAC2 protein Health aspects Histone deacetylase Histone Deacetylase 2 Histone Deacetylases - genetics Histone Deacetylases - physiology Histone H4 Histones - metabolism Human Genetics Humans Immunoprecipitation Internal Medicine Kinases Medicine Medicine & Public Health Microsatellite instability Microsatellite Repeats Molecular and cellular biology Molecular genetics Mutants Mutation Neoplasms - metabolism Neovascularization, Pathologic Oncology Physiological aspects Promoter Regions, Genetic Repressor Proteins - genetics Repressor Proteins - physiology Risk factors short-communication Transcription Factors - metabolism Transfection Tumor cell lines Tumorigenesis Tyrosine |
title | Transforming pathways unleashed by a HDAC2 mutation in human cancer |
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