title: Epigenetic mediated silencing of EYA4 contributes to tumorigenesis in oral dysplastic cells.
abstract: Five-year survival rates for oral squamous cell carcinoma (OSCC) have remained at a dismal 50% for the past several decades. Molecular analyses of premalignant tissues are a key means of identifying early foundational drivers of disease, which may be exploitable as biomarkers or therapeutic targets for improving disease outcomes. We previously identified EYA4 as frequently hypermethylated and silenced in premalignant disease based on an analysis of lesion-adjacent normal, dysplasia, and carcinoma in situ/squamous cell carcinoma tissues from the oral cavity. Herein, we further evaluate the role of this putative tumor suppressor gene in transformation of oral tissues and OSCC. By an initial assessment, EYA4 promoter hypermethylation was found in 24/32 (75%) of paired tumor samples in The Cancer Genome Atlas oral cancer data set, with significant correlation noted between methylation status and relative gene expression. To assess the impact of EYA4 in oral tumorigenesis, we overexpressed EYA4 in two oral dysplasia cell lines. Expression of EYA4 caused an increase in cell proliferation, DNA damage repair capabilities, and increased the level of apoptosis. Taken together, we find evidence that EYA4 is a novel tumor suppressor in oral cancer, which becomes methylated and silenced at the premalignant stage and appears to be epigenetically regulated. Further studies are warranted to investigate its role as a marker for progression in oral cancer. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Towle
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Truong
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.|Division of Otolaryngology, Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4E3, Canada.
authors.forename: Cathie
authors.initials: C
authors.lastname: Garnis
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: C117736:EYA4 protein, human; D012333:RNA, Messenger; D015534:Trans-Activators