HDAC-class II Specific Inhibition Involves HDAC Proteasome-Dependent Degradation Mediated by RANBP2

Biochim Biophys Acta. 2008 Oct;1783(10):2030-8. doi: 10.1016/j.bbamcr.2008.07.007. Epub 2008 Jul 22.

Abstract

Discovered for their ability to deacetylate histones and repress transcription, HDACs are a promising target for therapy of human diseases. The class II HDACs are mainly involved in developmental and differentiation processes, such as myogenesis. We report here that class I and class II HDAC inhibitors such as SAHA or the class II selective inhibitor MC1568 induce down-regulation of class II HDACs in human cells. In particular, both SAHA and MC1568 induce HDAC 4 down-regulation by increasing its specific sumoylation followed by activation of proteasomal pathways of degradation. Sumoylation that corresponds to HDAC 4 nuclear localization results in a transient increase of the HDAC 4 repressive action on target genes such as RARalpha and TNFalpha. The HDAC 4 degradation that follows to its sumoylation results in gene target activation. Silencing of the RANBP2 E3 ligase reverts HDAC 4 repression by blocking its own sumoylation. These findings identify a crosstalk occurring between acetylation, deacetylation and sumoylation pathways and suggest that class II specific HDAC inhibitors may affect different epigenetic pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / classification
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • SUMO-1 Protein / metabolism
  • Transcriptional Activation / genetics
  • Vorinostat

Substances

  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Molecular Chaperones
  • Nuclear Pore Complex Proteins
  • SUMO-1 Protein
  • ran-binding protein 2
  • Vorinostat
  • Proteasome Endopeptidase Complex
  • Histone Deacetylases