Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines.
Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1beta (HNF1beta), 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 HNF4alpha, a transcriptional target of HNF1beta, 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.
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
K
K
Terasawa
M
M
Toyota
S
S
Sagae
K
K
Ogi
H
H
Suzuki
T
T
Sonoda
K
K
Akino
R
R
Maruyama
N
N
Nishikawa
K
K
Imai
Y
Y
Shinomura
T
T
Saito
T
T
Tokino
D001483:Base Sequence; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D051539:Hepatocyte Nuclear Factor 1-beta / Q000096:biosynthesis* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured
C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta