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Transcriptional upregulation of histone deacetylase 2 promotes Myc-induced oncogenic effects

Oncogene volume 29, pages 5957–5968 (2010)Cite this article

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Abstract

Myc oncoproteins and histone deacetylases (HDACs) modulate gene transcription and enhance cancer cell proliferation, and HDAC inhibitors are among the most promising new classes of anticancer drugs. Here, we show that N-Myc and c-Myc upregulated HDAC2 gene expression in neuroblastoma and pancreatic cancer cells, respectively, which contributed to N-Myc- and c-Myc-induced cell proliferation. Cyclin G2 (CCNG2) was commonly repressed by N-Myc and HDAC2 in neuroblastoma cells and by c-Myc and HDAC2 in pancreatic cancer cells, and could be reactivated by HDAC inhibitors. 5-bromo-2′-deoxyuridine incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for N-Myc-, c-Myc- and HDAC2-induced cell proliferation. Dual crosslinking chromatin immunoprecipitation assay demonstrated that N-Myc acted as a transrepressor by recruiting the HDAC2 protein to Sp1-binding sites at the CCNG2 gene core promoter. Moreover, HDAC2 was upregulated, and CCNG2 downregulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc overexpression correlated with upregulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of upregulation of HDAC2 and suppression of CCNG2 in Myc-induced oncogenesis, and have significant implications for the application of HDAC inhibitors in the prevention and treatment of Myc-driven cancers.

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Acknowledgements

The authors are supported by an NIH project grant (T L), a Career Development and Support Fellowship from Cancer Institute NSW (T L and AVB), NHMRC (TL and GMM) and Cancer Council NSW (TL, AVB and CJS) project grants, NHMRC, Cancer Institute NSW and Cancer Council NSW programme grants (GMM, MH and MDN), Italian Association for Research on Cancer (GP), NHMRC Postdoctoral Training Fellowships (CJS and TT). 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, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia

    G M Marshall, N Xu, Z Neiron, T Trahair, P Y Liu, K Jankowski, M Haber, M D Norris, J Keating, E Sekyere, G Jonquieres & T Liu

  2. The Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, University of New South Wales, Sydney, New South Wales, Australia

    G M Marshall

  3. Department of Biology, University of Bologna, Via Selmi 3, Bologna, Italy

    S Gherardi, N Iraci & G Perini

  4. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    C J Scarlett, D K Chang & A V Biankin

  5. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    F Stossi & B S Katzenellenbogen

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  1. G M Marshall
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Marshall, G., Gherardi, S., Xu, N. et al. Transcriptional upregulation of histone deacetylase 2 promotes Myc-induced oncogenic effects. Oncogene 29, 5957–5968 (2010). https://doi.org/10.1038/onc.2010.332

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  • DOI: https://doi.org/10.1038/onc.2010.332

Keywords

  • N-Myc
  • c-Myc
  • histone deacetylase 2
  • cyclin G2
  • cell proliferation

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