DNA methylation and histone modification regulate silencing of epithelial cell adhesion molecule for tumor invasion and progression
Journal
Oncogene
Journal Volume
26
Journal Volume
26
Journal Issue
27
Journal Issue
27
Pages
3989-3997
Start Page
3989
End Page
3997
Date Issued
2007
Author(s)
Tai K.-Y.
Shiah S.-G.
Shieh Y.-S.
Kao Y.-R.
Chi C.-Y.
Huang E.
Lee H.-S.
Chang L.-C.
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.
Subjects
Ep-CAM; Invasion; Promoter methylation
SDGs
Other Subjects
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
Type
journal article