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Persistent downregulation of the pancarcinoma-associated epithelial cell adhesion molecule via active intranuclear methylation.
van der Gun, Bernardina T F; Wasserkort, Reinhold; Monami, Amélie; Jeltsch, Albert; Raskó, Tamás; Slaska-Kiss, Krystyna; Cortese, Rene; Rots, Marianne G; de Leij, Lou F M H; Ruiters, Marcel H J; Kiss, Antal; Weinhold, Elmar; McLaughlin, Pamela M J.
Afiliação
  • van der Gun BTF; Department of Pathology and Laboratory Medicine, Section Medical Biology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
  • Wasserkort R; Epigenomics AG, Kleine Praesidentenstrasse 1, D-10178, Berlin, Germany.
  • Monami A; Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany.
  • Jeltsch A; School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, D-28725 Bremen, Germany.
  • Raskó T; Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, 6726 Szeged, Temesvári krt. 62, Hungary.
  • Slaska-Kiss K; Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, 6726 Szeged, Temesvári krt. 62, Hungary.
  • Cortese R; Epigenomics AG, Kleine Praesidentenstrasse 1, D-10178, Berlin, Germany.
  • Rots MG; Department of Pathology and Laboratory Medicine, Section Medical Biology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
  • de Leij LFMH; Department of Pathology and Laboratory Medicine, Section Medical Biology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
  • Ruiters MHJ; Department of Pathology and Laboratory Medicine, Section Medical Biology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
  • Kiss A; Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, 6726 Szeged, Temesvári krt. 62, Hungary.
  • Weinhold E; Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany.
  • McLaughlin PMJ; Department of Pathology and Laboratory Medicine, Section Medical Biology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Int J Cancer ; 123(2): 484-489, 2008 Jul 15.
Article em En | MEDLINE | ID: mdl-18398839
The epithelial cell adhesion molecule (EpCAM) is expressed at high levels on the surface of most carcinoma cells. SiRNA silencing of EpCAM expression leads to reduced metastatic potential of tumor cells demonstrating its importance in oncogenesis and tumor progression. However, siRNA therapy requires either sequential delivery or integration into the host cell genome. Hence we set out to explore a more definite form to influence EpCAM gene expression. The mechanisms underlying the transcriptional activation of the EpCAM gene, both in normal epithelial tissue as well as in carcinogenesis, are poorly understood. We show that DNA methylation plays a crucial role in EpCAM expression, and moreover, active silencing of endogenous EpCAM via methylation of the EpCAM promoter results in a persistent downregulation of EpCAM expression. In a panel of carcinoma derived cell lines, bisulfite analyses showed a correlation between the methylation status of the EpCAM promoter and EpCAM expression. Treatment of EpCAM-negative cell lines with a demethylating agent induced EpCAM expression, both on mRNA and protein level, and caused upregulation of EpCAM expression in an EpCAM-positive cell line. After delivery of the DNA methyltransferase M.SssI into EpCAM-positive ovarian carcinoma cells, methylation of the EpCAM promoter resulted in silencing of EpCAM expression. SiRNA-mediated silencing remained for 4 days, after which EpCAM re-expression increased in time, while M.SssI-mediated downregulation of EpCAM maintained through successive cell divisions as the repression persisted for at least 17 days. This is the first study showing that active DNA methylation leads to sustained silencing of endogenous EpCAM expression.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma / Moléculas de Adesão Celular / Núcleo Celular / Metilação de DNA / Antígenos de Neoplasias Tipo de estudo: Risk_factors_studies Limite: Female / Humans Idioma: En Revista: Int J Cancer Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma / Moléculas de Adesão Celular / Núcleo Celular / Metilação de DNA / Antígenos de Neoplasias Tipo de estudo: Risk_factors_studies Limite: Female / Humans Idioma: En Revista: Int J Cancer Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Holanda