Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells
The Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in many cancers including ovarian cancer and EpCAM overexpression correlates with decreased survival of patients. It was the aim of this study to achieve a targeted methylation of the EpCAM promoter and silence EpCAM gene expression usin...
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| Veröffentlicht in: | PloS one 2014-01, Vol.9 (1), p.e87703-e87703 |
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| description | The Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in many cancers including ovarian cancer and EpCAM overexpression correlates with decreased survival of patients. It was the aim of this study to achieve a targeted methylation of the EpCAM promoter and silence EpCAM gene expression using an engineered zinc finger protein that specifically binds the EpCAM promoter fused to the catalytic domain of the Dnmt3a DNA methyltransferase. We show that transient transfection of this construct increased the methylation of the EpCAM promoter in SKOV3 cells from 4-8% in untreated cells to 30%. Up to 48% methylation was observed in stable cell lines which express the chimeric methyltransferase. Control experiments confirmed that the methylation was dependent on the fusion of the Zinc finger and the methyltransferase domains and specific for the target region. The stable cell lines with methylated EpCAM promoter showed a 60-80% reduction of EpCAM expression as determined at mRNA and protein level and exhibited a significantly reduced cell proliferation. Our data indicate that targeted methylation of the EpCAM promoter could be an approach in the therapy of EpCAM overexpressing cancers. |
| doi_str_mv | 10.1371/journal.pone.0087703 |
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It was the aim of this study to achieve a targeted methylation of the EpCAM promoter and silence EpCAM gene expression using an engineered zinc finger protein that specifically binds the EpCAM promoter fused to the catalytic domain of the Dnmt3a DNA methyltransferase. We show that transient transfection of this construct increased the methylation of the EpCAM promoter in SKOV3 cells from 4-8% in untreated cells to 30%. Up to 48% methylation was observed in stable cell lines which express the chimeric methyltransferase. Control experiments confirmed that the methylation was dependent on the fusion of the Zinc finger and the methyltransferase domains and specific for the target region. The stable cell lines with methylated EpCAM promoter showed a 60-80% reduction of EpCAM expression as determined at mRNA and protein level and exhibited a significantly reduced cell proliferation. Our data indicate that targeted methylation of the EpCAM promoter could be an approach in the therapy of EpCAM overexpressing cancers.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0087703</identifier><identifier>PMID: 24489952</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adhesion ; Antigens, Neoplasm - genetics ; Antigens, Neoplasm - metabolism ; Base Sequence ; Biology ; Biotechnology ; Cancer ; Catalysis ; Cell adhesion ; Cell adhesion & migration ; Cell adhesion molecules ; Cell Adhesion Molecules - genetics ; Cell Adhesion Molecules - metabolism ; Cell Line, Tumor ; Cell Proliferation ; Deoxyribonucleic acid ; DNA ; DNA binding proteins ; DNA Methylation ; DNA methyltransferase ; Epigenetics ; Epithelial Cell Adhesion Molecule ; Epithelial cells ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Genes ; Humans ; Medicine ; Methylation ; Methyltransferases ; Molecular Sequence Data ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms ; Promoter Regions, Genetic ; Protein binding ; RNA ; Sequence Analysis, DNA ; Silence ; Transfection ; Zinc ; Zinc finger proteins</subject><ispartof>PloS one, 2014-01, Vol.9 (1), p.e87703-e87703</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Nunna et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Nunna et al 2014 Nunna et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-8d89b149f2ac30d2a5e52967661e484558a228abfbd00c20013b5520e5d43ac53</citedby><cites>FETCH-LOGICAL-c659t-8d89b149f2ac30d2a5e52967661e484558a228abfbd00c20013b5520e5d43ac53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906225/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906225/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24489952$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tost, Jorg</contributor><creatorcontrib>Nunna, Suneetha</creatorcontrib><creatorcontrib>Reinhardt, Richard</creatorcontrib><creatorcontrib>Ragozin, Sergey</creatorcontrib><creatorcontrib>Jeltsch, Albert</creatorcontrib><title>Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in many cancers including ovarian cancer and EpCAM overexpression correlates with decreased survival of patients. It was the aim of this study to achieve a targeted methylation of the EpCAM promoter and silence EpCAM gene expression using an engineered zinc finger protein that specifically binds the EpCAM promoter fused to the catalytic domain of the Dnmt3a DNA methyltransferase. We show that transient transfection of this construct increased the methylation of the EpCAM promoter in SKOV3 cells from 4-8% in untreated cells to 30%. Up to 48% methylation was observed in stable cell lines which express the chimeric methyltransferase. Control experiments confirmed that the methylation was dependent on the fusion of the Zinc finger and the methyltransferase domains and specific for the target region. The stable cell lines with methylated EpCAM promoter showed a 60-80% reduction of EpCAM expression as determined at mRNA and protein level and exhibited a significantly reduced cell proliferation. Our data indicate that targeted methylation of the EpCAM promoter could be an approach in the therapy of EpCAM overexpressing cancers.</description><subject>Adhesion</subject><subject>Antigens, Neoplasm - genetics</subject><subject>Antigens, Neoplasm - metabolism</subject><subject>Base Sequence</subject><subject>Biology</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Catalysis</subject><subject>Cell adhesion</subject><subject>Cell adhesion & migration</subject><subject>Cell adhesion molecules</subject><subject>Cell Adhesion Molecules - genetics</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA binding proteins</subject><subject>DNA Methylation</subject><subject>DNA methyltransferase</subject><subject>Epigenetics</subject><subject>Epithelial Cell Adhesion Molecule</subject><subject>Epithelial cells</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Silencing</subject><subject>Genes</subject><subject>Humans</subject><subject>Medicine</subject><subject>Methylation</subject><subject>Methyltransferases</subject><subject>Molecular Sequence Data</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms</subject><subject>Promoter Regions, Genetic</subject><subject>Protein binding</subject><subject>RNA</subject><subject>Sequence Analysis, DNA</subject><subject>Silence</subject><subject>Transfection</subject><subject>Zinc</subject><subject>Zinc finger 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Jorg</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-01-29</date><risdate>2014</risdate><volume>9</volume><issue>1</issue><spage>e87703</spage><epage>e87703</epage><pages>e87703-e87703</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in many cancers including ovarian cancer and EpCAM overexpression correlates with decreased survival of patients. It was the aim of this study to achieve a targeted methylation of the EpCAM promoter and silence EpCAM gene expression using an engineered zinc finger protein that specifically binds the EpCAM promoter fused to the catalytic domain of the Dnmt3a DNA methyltransferase. We show that transient transfection of this construct increased the methylation of the EpCAM promoter in SKOV3 cells from 4-8% in untreated cells to 30%. Up to 48% methylation was observed in stable cell lines which express the chimeric methyltransferase. Control experiments confirmed that the methylation was dependent on the fusion of the Zinc finger and the methyltransferase domains and specific for the target region. The stable cell lines with methylated EpCAM promoter showed a 60-80% reduction of EpCAM expression as determined at mRNA and protein level and exhibited a significantly reduced cell proliferation. Our data indicate that targeted methylation of the EpCAM promoter could be an approach in the therapy of EpCAM overexpressing cancers.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24489952</pmid><doi>10.1371/journal.pone.0087703</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adhesion Antigens, Neoplasm - genetics Antigens, Neoplasm - metabolism Base Sequence Biology Biotechnology Cancer Catalysis Cell adhesion Cell adhesion & migration Cell adhesion molecules Cell Adhesion Molecules - genetics Cell Adhesion Molecules - metabolism Cell Line, Tumor Cell Proliferation Deoxyribonucleic acid DNA DNA binding proteins DNA Methylation DNA methyltransferase Epigenetics Epithelial Cell Adhesion Molecule Epithelial cells Female Gene expression Gene Expression Regulation, Neoplastic Gene Silencing Genes Humans Medicine Methylation Methyltransferases Molecular Sequence Data Ovarian cancer Ovarian carcinoma Ovarian Neoplasms Promoter Regions, Genetic Protein binding RNA Sequence Analysis, DNA Silence Transfection Zinc Zinc finger proteins |
| title | Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells |
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