HDAC-class II specific inhibition involves HDAC proteasome-dependent degradation mediated by RANBP2. - Archive ouverte HAL Access content directly
Journal Articles Biochimica et Biophysica Acta - Molecular Cell Research Year : 2008

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

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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.

Dates and versions

inserm-00351018 , version 1 (03-02-2009)

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Cite

Annamaria Scognamiglio, Angela Nebbioso, Fabio Manzo, Sergio Valente, Antonello Mai, et al.. HDAC-class II specific inhibition involves HDAC proteasome-dependent degradation mediated by RANBP2.. Biochimica et Biophysica Acta - Molecular Cell Research, 2008, 1783 (10), pp.2030-8. ⟨10.1016/j.bbamcr.2008.07.007⟩. ⟨inserm-00351018⟩
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