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EYA4 Acts as a New Tumor Suppressor Gene in Colorectal Cancer
Sung-Jin Kim1, Chung Hyun Tae2, Sung Noh Hong2
1Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
Abstract:
A previous genome-wide methylation array for colorectal cancer (CRC) identified aberrant promoter methylation of eyes absent 4 (EYA4). However, the correlations between EYA4 methylation and gene expression, the role played by EYA4 protein in colorectal carcinogenesis, and results of the gene-enrichment and functional annotation analysis have not yet been established. We analyzed the EYA4 methylation status and found EYA4 promoter methylation in CRC cell lines (100%), CRC tissues (93.5%) and advanced adenoma tissues (50.7%), compared with normal mucosa (32.6%). There was a significant inverse correlation between EYA4 methylation and expression. EYA4 transfection led to inhibition of cell proliferation in colony assays and xenograft studies. On performing the gene-enrichment and functional annotation analysis, we observed that the differentially expressed genes have been associated with the Wnt and MAPK signaling pathways. Our results demonstrate that EYA4 is under epigenetic regulation in CRC. It is a candidate tumor suppressor gene that acts by inducing up-regulation of DKK1 and inhibiting the Wnt signaling pathway. In addition, EYA4 methylation may be identified in stool samples and it serves as a potential stool biomarker for detection of advanced adenoma and CRC.
Insights
Epigenetic regulation of Eyes Absent 4 (EYA4) is crucial in colorectal cancer (CRC). EYA4 acts as a tumor suppressor by inhibiting Wnt signaling, showing potential as a biomarker for CRC and advanced adenoma detection.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Aberrant promoter methylation of Eyes Absent 4 (EYA4) was previously identified in colorectal cancer (CRC).
- The functional role of EYA4 in colorectal carcinogenesis and its correlation with gene expression remained unestablished.
Purpose of the Study:
- To investigate the correlation between EYA4 methylation and gene expression in CRC.
- To elucidate the role of EYA4 protein in colorectal carcinogenesis.
- To analyze gene-enrichment and functional pathways associated with EYA4.
Main Methods:
- Analysis of EYA4 promoter methylation status in CRC cell lines, tissues, and normal mucosa.
- Correlation analysis between EYA4 methylation and gene expression.
- Functional studies involving EYA4 transfection in cell proliferation assays and xenograft models.
- Gene-enrichment and functional annotation analysis.
Main Results:
- EYA4 promoter methylation was detected in 100% of CRC cell lines, 93.5% of CRC tissues, 50.7% of advanced adenomas, and 32.6% of normal mucosa.
- A significant inverse correlation was observed between EYA4 methylation and its expression.
- EYA4 transfection inhibited cell proliferation in vitro and in vivo.
- Differentially expressed genes were associated with Wnt and MAPK signaling pathways.
Conclusions:
- EYA4 is epigenetically regulated in CRC and functions as a tumor suppressor gene.
- EYA4 suppresses tumor growth by up-regulating DKK1 and inhibiting the Wnt signaling pathway.
- EYA4 methylation in stool samples presents a potential biomarker for detecting advanced adenoma and CRC.
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