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  • Original Paper
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Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Oncogene volume 23, pages 4380–4388 (2004)Cite this article

Abstract

The putative tumor suppressor CDKN1C is an imprinted gene at 11p15.5, a well-known imprinted region often deleted in tumors. The absence of somatic mutations and the frequent diminished expression in tumors would suggest that CDKN1C expression is regulated epigenetically. It has been, however, controversial whether the diminution is caused by imprinting disruption of the CDKN1C/LIT1 domain or by promoter hypermethylation of CDKN1C itself. To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines. CDKN1C expression was diminished in 10 of 17 lines and statistically correlated with the loss of methylation at DMR-LIT1 in all but three. However, there was no statistical correlation between CDKN1C promoter MI and CDKN1C expression. Furthermore, loss of CpG methylation was associated with loss of histone H3 lysine 9 (H3K9) methylation at DMR-LIT1. Histone modifications at CDKN1C promoter were not correlated with CDKN1C expression. The data suggested that the diminished CDKN1C expression is associated with the loss of methylation of CpG and H3K9 at DMR-LIT1, not by its own promoter CpG methylation, and is involved in esophageal cancer, implying that DMR-LIT1 epigenetically regulates CDKN1C expression not through histone modifications at CDKN1C promoter, but through that of DMR-LIT1.

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Acknowledgements

We thank Dr Y Shimada (Kyoto University), Drs T Abe and M Oka (Yamaguchi University School of Medicine), Drs T Fujii and H Yamana (Kurume University), Riken Gene Bank, and Cell Recourse Center for Biomedical Research Institute of Development, Aging and Cancer (Tohoku University) for kindly providing esophageal cancer cell lines. This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (#13206062) (TM) and from the Japan Society for the Promotion of Science (#13770069) (HS).

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Authors and Affiliations

  1. Department of Biomolecular Sciences, Division of Molecular Biology and Genetics, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan

    Hidenobu Soejima, Tetsuji Nakagawachi, Wei Zhao, Ken Higashimoto, Shiroh Matsukura, Keiichiro Joh & Tsunehiro Mukai

  2. Department of Biochemistry II, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan

    Takeshi Urano

  3. Department of Surgery, Division of General Surgery, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan

    Yoshihiko Kitajima & Kohji Miyazaki

  4. Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodou-cho, Izumi, Osaka, 594-1101, Japan

    Makoto Takeuchi & Masahiro Nakayama

  5. Department of Biomedical Science, Graduate School of Medical Science, Tottori University, 86 Nishimachi, 683-8503, Yonago, Japan

    Mitsuo Oshimura

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  1. Hidenobu Soejima
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Correspondence to Hidenobu Soejima.

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Soejima, H., Nakagawachi, T., Zhao, W. et al. Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer. Oncogene 23, 4380–4388 (2004). https://doi.org/10.1038/sj.onc.1207576

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