1. ¹Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan
2. ²Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo 060-8543, Japan
3. ³First Department of Internal Medicine, Sapporo Medical University, Sapporo 060-8543, Japan
4. ⁴PRESTO, JST, Kawaguchi, Japan
5. ⁵Department of Public Health, Sapporo 060-8543, Japan
6. ⁶First Department of Surgery, Sapporo Medical University, Sapporo 060-8543, Japan

Correspondence: Dr M Toyota, Department of Molecular Biology, Cancer Research Institute, South-1 West-17, Chuo-ku, Sapporo, Hokkaido, Japan. E-mail: mtoyota@sapmed.ac.jp

⁷These authors contributed equally to this work

Received 18 July 2005; Revised 22 November 2005; Accepted 16 January 2006; Published online 14 February 2006.

Abstract

Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1 (HNF1), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2'deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4, a transcriptional target of HNF1, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment.