title: EYA4 Acts as a New Tumor Suppressor Gene in Colorectal Cancer.
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.
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Chung Hyun
authors.initials: CH
authors.lastname: Tae
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sung Noh
authors.initials: SN
authors.lastname: Hong
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Min
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Dong Kyung
authors.initials: DK
authors.lastname: Chang
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Poong-Lyul
authors.initials: PL
authors.lastname: Rhee
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jae J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Center for Genome Research, Samsung Biomedical Research Institute, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Duk-Hwan
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000236:Adenoma / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C501126:DKK1 protein, human; C117736:EYA4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; D020928:Mitogen-Activated Protein Kinases
keywords: Colorectal cancer; EYA4 protein; Epigenetics; Tumor suppressor gene; Wnt signaling pathway