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

Oncogene volume 26, pages 3989–3997 (2007)Cite this article

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.

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Acknowledgements

This work was supported by grants from the National Health Research Institute 92A1-PAPP01-1, National Science Council NSC 95-2314-B-016-034, Tri-Service General Hospital TSGH-C95-24 and National Defense Medical Center DOD 95-01-04, Taiwan.

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Author notes

  1. K-Y Tai, S-G Shiah and Y-S Shieh: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Cancer Research, National Health Research Institutes, Miaoli, ROC, Taiwan

    K-Y Tai, S-G Shiah, Y-R Kao, C-Y Chi, E Huang & C-W Wu

  2. School of Dentistry and Cancer Epigenetic Laboratory, National Defense Medical Center, Taipei, Taiwan

    Y-S Shieh

  3. Department of Oral Diagnosis, Tri-service General Hospital, Taipei, Taiwan

    Y-S Shieh & L-C Chang

  4. Department of Pathology,

    H-S Lee

  5. Tri-service General Hospital, Taipei, Taiwan

    H-S Lee

  6. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    P-C Yang

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  1. K-Y Tai
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Correspondence to C-W Wu.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Tai, KY., Shiah, SG., Shieh, YS. et al. DNA methylation and histone modification regulate silencing of epithelial cell adhesion molecule for tumor invasion and progression. Oncogene 26, 3989–3997 (2007). https://doi.org/10.1038/sj.onc.1210176

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