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HES6 gene is selectively overexpressed in glioma and represents an important transcriptional regulator of glioma proliferation

Oncogene volume 31, pages 1299–1310 (2012)Cite this article

Abstract

Malignant glioma is the most common brain tumor with 16 000 new cases diagnosed annually in the United States. We performed a systematic large-scale transcriptomics data mining study of 9783 tissue samples from the GeneSapiens database to systematically identify genes that are most glioma-specific. We searched for genes that were highly expressed in 322 glioblastoma multiforme tissue samples and 66 anaplastic astrocytomas as compared with 425 samples from histologically normal central nervous system. Transcription cofactor HES6 (hairy and enhancer of split 6) emerged as the most glioma-specific gene. Immunostaining of a tissue microarray showed HES6 expression in 335 (98.8%) out of the 339 glioma samples. HES6 was expressed in endothelial cells of the normal brain and glioma tissue. Recurrent grade 2 astrocytomas and grade 2 or 3 oligodendrogliomas showed higher levels of HES6 immunoreactivity than the corresponding primary tumors. High HES6 mRNA expression correlated with the proneural subtype that generally has a favorable outcome but is prone to recur. Functional studies suggested an important role for HES6 in supporting survival of glioma cells, as evidenced by reduction of cancer cell proliferation and migration after HES6 silencing. The biological role and consequences of HES6 silencing and overexpression was explored with genome-wide analyses, which implicated a role for HES6 in p53, c-myc and nuclear factor-κB transcriptional networks. We conclude that HES6 is important for glioma cell proliferation and migration, and may have a role in angiogenesis.

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Acknowledgements

This work was supported by the Academy of Finland Translational Genome-Scale Biology Center of Excellence, the Sigrid Juselius foundation and EU-FP6 project RIGHT (LSHB-CT-2004-005276). We acknowledge Dr Bokkee Eun for the generous gift of the HES6 overexpression plasmid pEYFP-C1-Hes6 (Eun et al., 2008). We also acknowledge the Finnish DNA Microarray Centre for their excellent technical assistance.

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Authors and Affiliations

  1. Department of Medical Biotechnology, VTT Technical Research Centre of Finland and Centre for Biotechnology, University of Turku, Turku, Finland

    S Haapa-Paananen, S Kiviluoto, J P Mpindi, P Kohonen, M Perälä & O Kallioniemi

  2. Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    M Waltari, M Puputti & H Joensuu

  3. FIMM—Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    J P Mpindi & O Kallioniemi

  4. Department of Pathology, Helsinki University Central Hospital and Haartman Institute, University of Helsinki, Helsinki, Finland

    O Tynninen

  5. Department of Pathology, Tampere University Hospital, Tampere, Finland

    H Haapasalo

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  1. S Haapa-Paananen
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  2. S Kiviluoto
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Correspondence to S Haapa-Paananen.

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Haapa-Paananen, S., Kiviluoto, S., Waltari, M. et al. HES6 gene is selectively overexpressed in glioma and represents an important transcriptional regulator of glioma proliferation. Oncogene 31, 1299–1310 (2012). https://doi.org/10.1038/onc.2011.316

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  • DOI: https://doi.org/10.1038/onc.2011.316

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