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Stabilization of phenotypic plasticity through mesenchymal-specific DNA hypermethylation in cancer cells

Oncogene volume 31, pages 1963–1974 (2012)Cite this article

Abstract

The epithelial–mesenchymal transition (EMT) has a crucial role in normal and disease processes including tumor progression. In this study, we first classified epithelial-like and mesenchymal-like oral squamous cell carcinoma (OSCC) cell lines based on expression profiles of typical EMT-related genes using a panel of 18 OSCC cell lines. Then, we performed methylation-based and expression-based analyses of components of the Wnt signaling pathway, and identified WNT7A and WNT10A as genes silenced by mesenchymal-specific DNA hypermethylation in OSCCs. A significant association was revealed between some clinicopathological findings and the DNA methylation status of WNT7A (normal vs tumor, P=0.007; T1–2 vs T3–4, P=0.040; I–III vs IV, P=0.016) and WNT10A (N0–N1 vs N2–N3, P=0.046) in the advanced stages of OSCC. Moreover, we found that E-cadherin expression in cancer cells may be positively regulated by WNT7A, whose expression is negatively regulated by mesenchymal-specific DNA hypermethylation or ZEB1 in mesenchymal-like OSCC cells. Our findings indicate that epithelial-specific gene silencing through mesenchymal-specific DNA hypermethylation may stabilize the phenotypic plasticity of cancer cells during EMT/MET.

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Abbreviations

EMT:

epithelial–mesenchymal transition

MET:

mesenchymal-to-epithelial transition

OSCC:

oral squamous cell carcinoma

miRNA:

microRNA

5-aza-dCyd:

5-aza 2′-deoxycytidine

siRNA:

small interfering RNA

rhWNT7A:

recombinant human WNT7A

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Acknowledgements

We thank Ayako Takahashi and Rumi Mori for technical assistance. This study was supported in part by Grant-in-Aid for Scientific Research (A), (B) and (C), and Scientific Research on Priority Areas and Innovative Areas, and the Global Center of Excellence Program for International Research Center for Molecular Science in Tooth and Bone Diseases from the Ministry of Education, Culture, Sports, Science and Technology, Japan; a Health and Labour Sciences Research Grant by the Ministry of Health, Labour and Welfare, Japan; a grant from Core Research for Evolutional Science and Technology of the Japan Science and Technology Corporation; and a grant from the New Energy and Industrial Technology Development Organization.

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Authors and Affiliations

  1. Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Yushima Bunkyo-ku, Tokyo, Japan

    Y Kurasawa, K Kozaki, A Pimkhaokham, T Muramatsu, H Ono, T Ishihara, I Imoto & J Inazawa

  2. Department of Maxillofacial Surgery, Tokyo Medical and Dental University, Yushima Bunkyo-ku, Tokyo, Japan

    Y Kurasawa, N Uzawa & T Amagasa

  3. Department of Genome Medicine, Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Yushima Bunkyo-ku, Tokyo, Japan

    K Kozaki & J Inazawa

  4. Department of Oral and Maxillofacial surgery, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand

    A Pimkhaokham

  5. Global Center of Excellence (GCOE) Program for International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan

    J Inazawa

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  1. Y Kurasawa
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Correspondence to J Inazawa.

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Kurasawa, Y., Kozaki, K., Pimkhaokham, A. et al. Stabilization of phenotypic plasticity through mesenchymal-specific DNA hypermethylation in cancer cells. Oncogene 31, 1963–1974 (2012). https://doi.org/10.1038/onc.2011.373

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