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Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines
K Terasawa1, M Toyota, S Sagae
1Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Abstract:
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.
Insights
Epigenetic silencing of the Transcription Factor 2 gene (TCF2) inactivates its tumor-suppressing role in ovarian cancer. Restoring TCF2 expression may offer a new therapeutic strategy for cancer treatment.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The Transcription Factor 2 (TCF2) gene encodes hepatocyte nuclear factor 1beta (HNF1beta), a key regulator of development and metabolism.
- TCF2 mutations are linked to renal cell cancer, and its epigenetic alterations are implicated in various cancers.
Purpose of the Study:
- To investigate the role of TCF2 epigenetic inactivation in ovarian cancer development.
- To explore the potential of TCF2 as a biomarker and therapeutic target in ovarian cancer.
Main Methods:
- Screening for aberrantly methylated genes in ovarian cancer.
- Assessing TCF2 methylation status in cell lines and primary tumors using methylation-specific assays.
- Evaluating TCF2 gene expression levels.
- Utilizing methyltransferase inhibitors (5-aza-dC) and histone deacetylase inhibitors (trichostatin A) to restore gene expression.
- Employing chromatin immunoprecipitation to analyze histone modifications.
Main Results:
- TCF2 was found to be epigenetically inactivated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, leading to reduced gene expression.
- Treatment with 5-aza-dC restored TCF2 expression, while combined treatment with 5-aza-dC and trichostatin A showed synergistic effects.
- Epigenetic inactivation of TCF2 was also observed in colorectal, gastric, and pancreatic cancer cell lines.
- Restoration of TCF2 expression led to the induction of HNF4alpha, a downstream target, indicating disruption of the HNF network.
Conclusions:
- Epigenetic silencing of TCF2 is a significant mechanism in ovarian tumorigenesis.
- TCF2 inactivation impacts the HNF network, suggesting its broader role in cancer development.
- TCF2 represents a potential diagnostic marker and therapeutic target for ovarian cancer and possibly other malignancies.
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