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

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.

Histone Deacetylase Classes I and II Regulate Kaposi's Sarcoma-Associated Herpesvirus Reactivation

“…SML0065), and sodium butyrate (nBA; catalog no. B5887) were from Sigma; HC toxin (sc-200884) was from Santa Cruz Biotechnology; and MC 1568 was a gift from Lucia Altucci (30).…”

“…To determine which HDAC classes regulate KSHV latency and reactivation, we treated infected cells with a series of HDACis that have various specificities (Table 2) (7,26,30,41). We measured KSHV reactivation in the Vero-rKSHV.219 cell line, which enables easy quantitation by scoring induction of an early (E) PAN promoter reporter cassette that drives expression of the red fluorescent protein (RFP) (29).…”

Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation

“…The apoptotic cells Annexin V-positive/propidium iodide-negative were considered. Recycling experiments: after treatment of the cells, the medium was replaced with fresh medium and the cells remained in culture for an additional 24 and 48 h. Samples were acquired on an FACS-Calibur flow cytometer using the Cell Quest software (Becton Dickinson, Milan, Italy) and analysed by standard procedures using the same software and the ModFit LT version 3 Software (Verity, Topsham, ME, USA) as previously reported Scognamiglio et al, 2008).…”

“…The ribonuclease (RNase) Protection Assay was performed according to standard procedures (Pharmingen, San Diego, CA, USA) as previously reported (Altucci et al, 2001;Scognamiglio et al, 2008). Probes used for specific HDAC detection in rats are available on request.…”

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

“…HDACi treatment can alter proteasomal degradation of various proteins, either enhancing or inhibiting their degradation. [27][28][29][30][31][32] Therefore, we investigated whether the increase in Dicer protein expression by Panobinostat was a result of diminished proteasomal degradation. Bortezomib, a well-known and clinically relevant inhibitor of proteasomal degradation, was chosen for these studies.…”