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Histone deacetylase 5 blocks neuroblastoma cell differentiation by interacting with N-Myc

Oncogene volume 33, pages 2987–2994 (2014)Cite this article

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Abstract

The N-Myc oncoprotein induces neuroblastoma, which arises from undifferentiated neuroblasts in the sympathetic nervous system, by modulating gene and protein expression and consequently causing cell differentiation block and cell proliferation. The class IIa histone deacetylase 5 (HDAC5) represses gene transcription, and blocks myoblast, osteoblast and leukemia cell differentiation. Here we showed that N-Myc upregulated HDAC5 expression in neuroblastoma cells. Conversely, HDAC5 repressed the ubiquitin–protein ligase NEDD4 gene expression, increased Aurora A gene expression and consequently upregulated N-Myc protein expression. Genome-wide gene expression analysis and protein co-immunoprecipitation assays revealed that HDAC5 and N-Myc repressed the expression of a common subset of genes by forming a protein complex, whereas HDAC5 and the class III HDAC SIRT2 independently repressed the expression of another common subset of genes without forming a protein complex. Moreover, HDAC5 blocked differentiation and induced proliferation in neuroblastoma cells. Taken together, our data identify HDAC5 as a novel co-factor in N-Myc oncogenesis, and provide the evidence for the potential application of HDAC5 inhibitors in the therapy of N-Myc-induced neuroblastoma and potentially other c-Myc-induced malignancies.

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Acknowledgements

We thank Dr Eric Olsen for the HDAC5 expression constructs. This work was supported by a National Health and Medical Research Council project grant 1006002 (T Liu and CJ Scarlett) and a Cancer Council NSW project grant. T Liu is a recipient of an ARC Future Fellowship, AV Biankin and CJ Scarlett are recipients of Cancer Institute New South Wales Fellowships. Children’s Cancer Institute Australia is affiliated with University of New South Wales and Sydney Children’s Hospital.

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Authors and Affiliations

  1. Children’s Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia

    Y Sun, P Y Liu, A Malyukova, B Liu, G M Marshall, K L MacKenzie & T Liu

  2. School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia

    C J Scarlett

  3. Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    C J Scarlett & A V Biankin

  4. Kids Cancer Alliance, Randwick, New South Wales, Australia

    B Liu

  5. Kids Cancer Centre, Sydney Children’s Hospital, Randwick, New South Wales, Australia

    G M Marshall

  6. Department of Surgery, Bankstown Hospital, Bankstown, New South Wales, Australia

    A V Biankin

  7. South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia

    A V Biankin

  8. School of Women’s and Children’s Health, UNSW Medicine, University of New South Wales, Randwick, New South Wales, Australia

    T Liu

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  1. Y Sun
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Sun, Y., Liu, P., Scarlett, C. et al. Histone deacetylase 5 blocks neuroblastoma cell differentiation by interacting with N-Myc. Oncogene 33, 2987–2994 (2014). https://doi.org/10.1038/onc.2013.253

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