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  • Oncogenomics
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Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma

Oncogene volume 22, pages 6946–6953 (2003)Cite this article

Abstract

Promoter hypermethylation has become apparent as a common mechanism of gene silencing in cancer. Based on our published microarray expression data, we noticed a prominent downregulation of ID4 in gastric adenocarcinoma. The dense 5′ CpG island covering the previously mapped upstream promoter of ID4 has prompted us to relate its downregulation to promoter hypermethylation. ID proteins are distinct members in the helix–loop–helix family of transcriptional regulators, which modulate various key developmental processes. Emerging data have suggested the involvement of ID genes in tumorigenesis. In this study using bisulfite genomic sequencing, we have found hypermethylation of ID4 promoter in most gastric cancer cell lines and 30% of primary tumors. This correlated with decreased level of ID4 expression. Restoration of ID4 expression in various gastric cancer cell lines was achieved by treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine, which at times required the synergistic action of the histone deacetylase inhibitor trichostatin A, but not with trichostatin A alone. Re-expression was accompanied by the corresponding ID4 promoter demethylation. Furthermore, we have found significant association of ID4 promoter methylation with hMLH1 promoter methylation (P=0.008) and microsatellite instability (P=0.006). Overall, our results have shown that transcriptional silencing of ID4 is related to the aberrant methylation of its promoter in gastric cancer. The significant association of ID4 and hMLH1 promoter hypermethylation suggested that ID4 may also be among the genes being targeted in the CpG island methylator phenotype tumorigenic pathway.

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Acknowledgements

This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region (HKU 7006/99M and 7264/01M) and the HM Lui Foundation.

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Authors and Affiliations

  1. Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong

    Agnes Sze Wah Chan, Wai Yin Tsui, Tsun Leung Chan, Annie Shuk Yee Chan, Siu Tsan Yuen & Suet Yi Leung

  2. Department of Surgery, Stanford University School of Medicine, Stanford, 94305, CA, USA

    Xin Chen, Rui Li & Samuel So

  3. Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong

    Kent Man Chu

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  1. Agnes Sze Wah Chan
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Correspondence to Siu Tsan Yuen or Suet Yi Leung.

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Chan, A., Tsui, W., Chen, X. et al. Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma. Oncogene 22, 6946–6953 (2003). https://doi.org/10.1038/sj.onc.1206799

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