Disruption of HDAC4/N-CoR complex by histone deacetylase inhibitors leads to inhibition of IL-2 gene expression

Biochem Pharmacol. 2007 Aug 1;74(3):465-76. doi: 10.1016/j.bcp.2007.05.002. Epub 2007 May 6.


Previous studies have shown that HDAC inhibitors selectively inhibit IL-2 gene expression, but the mechanism of this inhibition remains to be elucidated. It was recently reported that HDAC4, a component of the nuclear hormone receptor corepressor (N-CoR) complex, associates with the IL-2 promoter via the transcription factor myocyte enhancer factor 2 (MEF2). We therefore focused on the role of HDAC4/N-CoR complex in the transcriptional regulation of IL-2. Four approaches were used to characterize this role and to investigate the relation between the regulatory function of HDAC4/N-CoR complex and HDAC4-enzymatic activity: (i) HDAC4 silencing by RNA interference, (ii) overexpression of N-CoR repression domain 3 (RD3), (iii) overexpression of HDAC4 point mutants, and (iv) treatment with HDAC inhibitors. Here, we report that HDAC4 plays an essential role in IL-2 promoter activation, and that the formation of the HDAC4/N-CoR complex, which is closely related to HDAC4-enzymatic activity, might be involved in HDAC inhibitor-mediated inhibition of IL-2 gene expression. These observations indicate that the selective inhibition of HDAC4 or the interaction of HDAC4 with N-CoR is likely a potential target for the development of novel immunosuppressants.

Publication types

  • Historical Article

MeSH terms

  • Base Sequence
  • Cell Line
  • DNA Primers
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Gene Silencing
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / genetics
  • History, 15th Century
  • Humans
  • Interleukin-2 / genetics*
  • Mutation
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Receptor Co-Repressor 1
  • Peptides, Cyclic / pharmacology
  • Promoter Regions, Genetic
  • RNA, Small Interfering
  • Repressor Proteins / antagonists & inhibitors*


  • DNA Primers
  • Enzyme Inhibitors
  • FR 235222
  • Histone Deacetylase Inhibitors
  • Interleukin-2
  • NCOR1 protein, human
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Peptides, Cyclic
  • RNA, Small Interfering
  • Repressor Proteins
  • Histone Deacetylases