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Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2

Oncogene volume 27, pages 4200–4209 (2008)Cite this article

Abstract

Tumor hypoxia has been reported to cause a functional loss in DNA mismatch repair (MMR) system as a result of downregulation of MMR genes, although the precise molecular mechanisms remain unclear. In this study, we focused on the downregulation of a key MMR gene, MLH1, and demonstrated that hypoxia-inducible transcription repressors, differentiated embryo chondrocytes (DEC1 and 2), participated in its transcriptional regulation via their bindings to E-box-like motif(s) in MLH1 promoter region. In all cancer cell lines examined, hypoxia increased expression of DEC1 and 2, known as hypoxia-inducible genes, but decreased MLH1 expression in an exposure time-dependent manner at both the mRNA and protein levels. Co-transfection reporter assay revealed that DEC1 and, to greater extent, DEC2 as well as hypoxia-repressed MLH1 promoter activity. We further found that the action was remarkably inhibited by trichostatin A, and identified a possible DEC-response element in the MLH1 promoter. In vitro electrophoretic gel mobility shift and chromatin immunoprecipitation assays demonstrated that DEC1 or 2 directly bounds to the suggested element, and transient transfection assay revealed that overexpression of DEC2 repressed endogenous MLH1 expression in the cells. Hypoxia-induced DEC may impair MMR function through repression of MLH1 expression, possibly via the histone deacethylase-mediated mechanism in cancer cells.

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Acknowledgements

We thank Dr H Eguchi (Saitama Medical University), Dr S Tashiro, Dr N Oue, Dr K Miyazaki (Hiroshima University), Dr Y Makino (Asahikawa Medical College) and Dr K Igarashi (Tohoku University) for their helpful contributions to this work. We also thank Ms I Fukuba, Ms K Nukata, Ms C Oda, Ms M Wada and Ms M Sasaki for their technical and secretarial support. A part of this work was carried out at the Analysis Center of Life Science, Hiroshima University. This work was supported by Grants-in-Aid for Exploratory Research from Japan Society for the Promotion of Science and Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Translational Cancer Research, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    H Nakamura, K Tanimoto, K Hiyama, M Yunokawa & M Nishiyama

  2. Department of Dental and Medical Biochemistry, Hiroshima University, Hiroshima, Japan

    T Kawamoto & Y Kato

  3. Department of Molecular Oral Medicine and Maxillofacial Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

    K Yoshiga

  4. Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden

    L Poellinger

  5. Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan

    H Nakamura & E Hiyama

  6. Saitama Medical University International Medical Center, Saitama, Japan

    M Nishiyama

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  1. H Nakamura
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Correspondence to K Tanimoto.

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Nakamura, H., Tanimoto, K., Hiyama, K. et al. Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2. Oncogene 27, 4200–4209 (2008). https://doi.org/10.1038/onc.2008.58

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