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Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

Oncogene volume 29, pages 2681–2690 (2010)Cite this article

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Abstract

Recent advances in neuroblastoma (NB) research addressed that epigenetic alterations such as hypermethylation of promoter sequences, with consequent silencing of tumor-suppressor genes, can have significant roles in the tumorigenesis of NB. However, the exact role of epigenetic alterations, except for DNA hypermethylation, remains to be elucidated in NB research. In this paper, we clarified the direct binding of MYCN to Bmi1 promoter and upregulation of Bmi1 transcription by MYCN. Mutation introduction into an MYCN binding site in the Bmi1 promoter suggests that MYCN has more important roles in the transcription of Bmi1 than E2F-related Bmi1 regulation. A correlation between MYCN and polycomb protein Bmi1 expression was observed in primary NB tumors. Expression of Bmi1 resulted in the acceleration of proliferation and colony formation in NB cells. Bmi1-related inhibition of NB cell differentiation was confirmed by neurite extension assay and analysis of differentiation marker molecules. Intriguingly, the above-mentioned Bmi1-related regulation of the NB cell phenotype seems not to be mediated only by p14ARF/p16INK4a in NB cells. Expression profiling analysis using a tumor-specific cDNA microarray addressed the Bmi1-dependent repression of KIF1Bβ and TSLC1, which have important roles in predicting the prognosis of NB. Chromatin immunoprecipitation assay showed that KIF1Bβ and TSLC1 are direct targets of Bmi1 in NB cells. These findings suggest that MYCN induces Bmi1 expression, resulting in the repression of tumor suppressors through Polycomb group gene-mediated epigenetic chromosome modification. NB cell proliferation and differentiation seem to be partially dependent on the MYCN/Bmi1/tumor-suppressor pathways.

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Acknowledgements

We thank K Sakurai for technical assistance, and Daniel Mrozek, Medical English Service, for editorial assistance. This study was supported in part by a grant-in-aid from the Sankyo Foundation of Life Science, a grant-in-aid from the Ministry of Health, Labor, and Welfare for Third Term Comprehensive Control Research for Cancer, a grant-in-aid for Cancer Research (20–13) from the Ministry of Health, Labor, and Welfare of Japan, and a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan

    H Ochiai, H Takenobu, Y Yamaguchi, M Kimura & T Kamijo

  2. Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan

    H Ochiai & Y Kohno

  3. Department of Pathology, National Center for Child Health and Development, Tokyo, Japan

    A Nakagawa

  4. Laboratory of Cancer Genomics, Chiba Cancer Center Research Institute, Chiba, Japan

    M Ohira

  5. Department of Hematology and Oncology, Chiba Children's Hospital, Chiba, Japan

    Y Okimoto

  6. Developmental Genetics Group, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

    Y Fujimura & H Koseki

  7. Division of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba, Japan

    A Nakagawara

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Correspondence to T Kamijo.

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Ochiai, H., Takenobu, H., Nakagawa, A. et al. Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma. Oncogene 29, 2681–2690 (2010). https://doi.org/10.1038/onc.2010.22

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