1. ¹Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC
2. ²School of Dentistry and Cancer Epigenetic Laboratory, National Defense Medical Center, Taipei, Taiwan
3. ³Department of Oral Diagnosis, Tri-service General Hospital, Taipei, Taiwan
4. ⁴Department of Pathology, Tri-service General Hospital, Taipei, Taiwan
5. ⁵Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Correspondence: Dr C-W Wu, Institute of Cancer Research, National Health Research Institutes or Dr Y-S Shieh, National Defense Medical Center, 116, Sec 6, Michuan E Road, Taiwan, ROC. E-mail: ken@nhri.org.tw or ndmcyss@ndmctsgh.edu.tw

⁶These authors contributed equally to this work.

Received 19 June 2006; Revised 5 October 2006; Accepted 23 October 2006; Published online 8 January 2007.

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.