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

Oncogene. 2014 Jun 5;33(23):2987-94. doi: 10.1038/onc.2013.253. Epub 2013 Jul 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • HEK293 Cells
  • Histone Deacetylases / metabolism*
  • Humans
  • N-Myc Proto-Oncogene Protein
  • Nedd4 Ubiquitin Protein Ligases
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / metabolism*
  • Sirtuin 2 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Endosomal Sorting Complexes Required for Transport
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Ubiquitin-Protein Ligases
  • AURKA protein, human
  • Aurora Kinase A
  • SIRT2 protein, human
  • Sirtuin 2
  • HDAC5 protein, human
  • Histone Deacetylases