|Title:||DNA methylation and histone modification regulate silencing of epithelial cell adhesion molecule for tumor invasion and progression||Authors:||Tai K.-Y.
|Keywords:||Ep-CAM; Invasion; Promoter methylation||Issue Date:||2007||Journal Volume:||26||Journal Issue:||27||Start page/Pages:||3989-3997||Source:||Oncogene||Abstract:||
Epithelial cell adhesion molecule (Ep-CAM) is believed to have a critical role in carcinogenesis and cell proliferation. However, the association of Ep-CAM with cancer invasion and progression is less clear. We found that Ep-CAM was highly expressed on low-invasive cells compared with highly invasive cells. Forced expression of Ep-CAM decreased cancer invasiveness, and silencing Ep-CAM expression elevated cancer invasiveness. Ep-CAM expression was associated with promoter methylation. Treatment with a demethylating agent, and/or the histone deacetylase inhibitor reactivated Ep-CAM expression in Ep-CAM-negative cells and inhibited cancer invasiveness. Using a promoter-reporter construct, we demonstrated methylation of the promoter fragment drive Ep-CAM-silenced transcription. Additionally, silenced Ep-CAM gene in cancer cells was enriched for hypermethylated histone 3 lysine 9. When unmethylated and active, this promoter was associated with acetylated histone 3 lysine 9. Furthermore, we observed an increased association of Ep-CAM promoter with repression components as tumor invasiveness increased. In cancer tissues, Ep-CAM expression significantly correlated with tumor progression and associated with promoter methylation. Our data support the idea that modulation of Ep-CAM plays a pivotal role in tumor invasion and progression. Moreover, aberrant DNA methylation of Ep-CAM is implicated in enhancing invasive/metastatic proclivity of tumors. ? 2007 Nature Publishing Group All rights reserved.
|ISSN:||0950-9232||DOI:||10.1038/sj.onc.1210176||SDG/Keyword:||epithelial cell adhesion molecule; histone; histone H3; lysine; acetylation; article; cancer growth; cancer invasion; controlled study; correlation analysis; DNA methylation; female; gene expression; gene repression; gene silencing; genetic transcription; human; human cell; priority journal; promoter region; reporter gene; Antigens, Neoplasm; Blotting, Western; Cell Adhesion Molecules; Cell Line, Tumor; Cell Movement; Disease Progression; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins; Histones; Humans; Immunohistochemistry; Luciferases; Lung Neoplasms; Male; Neoplasm Invasiveness; Promoter Regions (Genetics); Protein Processing, Post-Translational; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transfection
|Appears in Collections:||醫學系|
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