DNA methylation and histone modification regulate silencing of epithelial cell adhesion molecule for tumor invasion and progression

K. Y. Tai, S. G. Shiah, Y. S. Shieh*, Y. R. Kao, C. Y. Chi, E. Huang, H. S. Lee, L. C. Chang, P. C. Yang, Cheng-Wen Wu Lee

*Corresponding author for this work

Research output: Contribution to journalArticle

50 Scopus citations

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.

Original languageEnglish
Pages (from-to)3989-3997
Number of pages9
JournalOncogene
Volume26
Issue number27
DOIs
StatePublished - 7 Jun 2007

Keywords

  • Ep-CAM
  • Invasion
  • Promoter methylation

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    Tai, K. Y., Shiah, S. G., Shieh, Y. S., Kao, Y. R., Chi, C. Y., Huang, E., Lee, H. S., Chang, L. C., Yang, P. C., & Wu Lee, C-W. (2007). DNA methylation and histone modification regulate silencing of epithelial cell adhesion molecule for tumor invasion and progression. Oncogene, 26(27), 3989-3997. https://doi.org/10.1038/sj.onc.1210176