Transcription factors and molecular epigenetic marks underlying EpCAM overexpression in ovarian cancer

• Published in: British journal of cancer Vol. 105; no. 2; pp. 312 - 319
• Main Authors: van der Gun, B T F, de Groote, M L, Kazemier, H G, Arendzen, A J, Terpstra, P, Ruiters, M H J, McLaughlin, P M J, Rots, M G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.07.2011; Nature Publishing Group
• Subjects: 692/420/2489/2487/2486; 692/699/67/1517/1709; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Base Sequence; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma - genetics; Carcinoma - metabolism; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Line, Tumor; DNA Methylation - physiology; Drug Resistance; Epidemiology; Epigenesis, Genetic - physiology; Epithelial Cell Adhesion Molecule; Female; Female genital diseases; Gene Expression Regulation, Neoplastic; Genetic Markers - physiology; Genetics and Genomics; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Models, Biological; Molecular Medicine; Molecular Sequence Data; Oncology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Tumors; Up-Regulation - genetics; DNA methylation; histone modifications; EpCAM; ovarian cancer; transcription factors; Modification; Ovary cancer; Gene overexpression; Malignant tumor; Female genital diseases; Ovarian diseases; Signal transduction; Cancerology; DNA; Epigenetics; Transcription factor; Histone; Methylation; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.231

Background: The epithelial cell adhesion molecule (EpCAM) is overexpressed on carcinomas, and its downregulation inhibits the oncogenic potential of multiple tumour types. Here, we investigated underlying mechanisms of epcam overexpression in ovarian carcinoma. Methods: Expression of EpCAM and DNA methylation (bisulphite sequencing) was determined for ovarian cancer cell lines. The association of histone modifications and 16 transcription factors with the epcam promoter was analysed by chromatin immunoprecipitation. Treatment with 5-Aza-2′-deoxycytidine (5-AZAC) was used to induce EpCAM expression. Results: Expression of EpCAM was correlated with DNA methylation and histone modifications. Treatment with 5-AZAC induced EpCAM expression in negative cells. Ten transcription factors were associated with the epcam gene in EpCAM expressing cells, but not in EpCAM-negative cells. Methylation of an Sp1 probe inhibited the binding of nuclear extract proteins in electromobility shift assays; such DNA methylation sensitivity was not observed for an NF- κ B probe. Conclusion: This study provides insights in transcriptional regulation of epcam in ovarian cancer. Epigenetic parameters associated with EpCAM overexpression are potentially reversible, allowing novel strategies for sustained silencing of EpCAM expression.