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  • Original Paper
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The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14ARF, p16INK4a and RASSF1A in human lung cancer cell lines

Oncogene volume 21, pages 4822–4829 (2002)Cite this article

Abstract

Promoter hypermethylation is an important means for the transcriptional repression of a number of cancer-associated genes. However, the underlying mechanism of this aberration in cancer remains unclear. Here, we examined 5′ CpG island methylation status and expression of the p14ARF, p16INK4a and RASSF1A tumor suppressor genes, and investigated the relationship of these factors with the mRNA expression of DNA methyltransferases (DNMTs) and/or methyl-CpG-binding proteins (MBPs) in 30 lung cancer cell lines including 12 small cell lung cancers (SCLCs) and 18 non-small cell lung cancers (NSCLCs). When β-actin was used as an internal control, the mRNA expression of three DNMTs (DNMT1, DNMT3A, and DNMT3B) and five MBPs (MBD1, MBD2, MBD3, MBD4, and MeCP2) was upregulated in SCLC, while only that of DNMT1, DNMT3B and MBD3 was upregulated in NSCLC, compared with normal lung tissues. However, when normalized using proliferating cell nuclear antigen (PCNA) as an internal control, these differences disappeared or diminished; there was even a significant reduction in the expression ratios of DNMT1, MBD2 and MeCP2 in SCLC and DNMT1, MBD2 and MBD4 in NSCLC. Furthermore, although significant correlations between PCNA expression and mRNA expression levels of the three DNMTs and four of the MBPs (excluding MeCP2) were observed, there was no obvious correlation between promoter hypermethylation of these tumor suppressor genes and the expression level of any of the DNMTs or MBPs. Our results suggest that upregulation of DNMTs and MBPs probably reflects an increased cell proliferation in human lung cancers and that there are likely to exist gene-specific mechanisms for epigenetic gene silencing.

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Abbreviations

SCLC:

small cell lung cancer

CDK:

cyclin-dependent kinase

NSCLC:

non-small cell lung cancer

RASSF1 :

Ras association domain family 1

DNMT :

DNA methyltransferase

MBP :

methyl-CpG-binding protein

PCNA :

proliferating cell nuclear antigen

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Acknowledgements

The authors thank Dr Chaubert for giving us technical advice for bisulfite genomic sequencing, and Keiko Shimamoto for her technical assistance. This work was supported in part by a Grant-in-Aid from Japan Society for Promotion of Science (to Y Sekido), a grant from Kanae Foundation for Life & Socio-medical Science, (to Y Sekido), grants NCI P50 CA70907 and CA71618 (to JD Minna) and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (to Y Hasegawa).

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  1. Yoshitsugu Horio

    Present address: Department of Internal Medicine, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, 464-8681, Nagoya, Japan

Authors and Affiliations

  1. Department of Clinical Preventive Medicine, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, 466-8550, Nagoya, Japan

    Mitsuo Sato, Yoshitaka Sekido & Kaoru Shimokata

  2. First Department of Internal Medicine, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, 466-8550, Nagoya, Japan

    Yoshitsugu Horio & Yoshinori Hasegawa

  3. Hamon Center for Therapeutic Oncology Research, University of Texas, Southwestern Medical Center, Dallas, 75390-8593, Texas, TX, USA

    John D Minna

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  1. Mitsuo Sato
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Correspondence to Yoshitsugu Horio.

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Sato, M., Horio, Y., Sekido, Y. et al. The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14ARF, p16INK4a and RASSF1A in human lung cancer cell lines. Oncogene 21, 4822–4829 (2002). https://doi.org/10.1038/sj.onc.1205581

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