HDAC-class II specific inhibition involves HDAC proteasome-dependent degradation mediated by RANBP2.
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.
Scognamiglio
Annamaria
A
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. De Crecchio 7, 80138 Napoli, Italy.
Nebbioso
Angela
A
Manzo
Fabio
F
Valente
Sergio
S
Mai
Antonello
A
Altucci
Lucia
L
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000145:classification / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D025842:SUMO-1 Protein / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D000077337:Vorinostat
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D025842:SUMO-1 Protein; C094493:ran-binding protein 2; D000077337:Vorinostat; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases