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

HDAC-class II specific inhibition involves HDAC proteasome-dependent degradation mediated by RANBP2.

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1
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. De Crecchio 7, 80138 Napoli, Italy.

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.

PMID:
18691615
DOI:
10.1016/j.bbamcr.2008.07.007
[Indexed for MEDLINE]
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