Inhibition of Histone Deacetylases by Chlamydocin Induces Apoptosis and Proteasome-Mediated Degradation of Survivin

Abstract

The naturally occurring cyclic tetrapeptide chlamydocin is a very potent inhibitor of cell proliferation. Here we show that chlamydocin is a highly potent histone deacetylase (HDAC) inhibitor, inhibiting HDAC activity in vitro with an IC 50 of 1.3 nM. Like other HDAC inhibitors, chlamydocin induces the accumulation of hyperacetylated histones H3 and H4 in A2780 ovarian cancer cells, increases the expression of p21 cip1/waf1 , and causes an accumulation of cells in G 2 /M phase of the cell cycle. In addition, chlamydocin induces apoptosis by activating caspase-3, which in turn leads to the cleavage of p21 cip1/waf1 into a 15-kDa breakdown product and drives cells from growth arrest into apoptosis. Concomitant with the activation of caspase-3 and cleavage of p21 cip1/waf1 , chlamydocin decreases the protein level of survivin, a member of the inhibitor of apoptosis protein family that is selectively expressed in tumors. Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors, stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21 cip1/waf1 induced by chlamydocin treatment. The decrease of survivin protein level is mediated by degradation via proteasomes since it can be inhibited by specific proteasome inhibitors. Taken together, our results show that induction of apoptosis by chlamydocin involves caspase-dependent cleavage of p21 cip1/waf1 , which is strikingly associated with proteasomemediated degradation of survivin.

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

“…Furthermore, recruitment of TRAIL-R2, FADD, and caspase-8 to the DISC following lexatumumab treatment was not impaired in the absence of p21. These results suggest that p21 may promote lexatumumab-induced cell death at a point downstream of DISC formation, and other studies have shown that HDAC inhibitors down-regulate the expression of the IAPs, XIAP and survivin (38)(39)(40)(41). In agreement with these reports, we also observed a decrease in these two proteins following treatment with SAHA.…”

Apicidin Induces Apoptosis via Cytochrome c-Mediated Intrinsic Pathway in Human Ovarian Cancer Cells

“…In particular, we observed that caspase-3 activation increased during apicidin-induced apoptosis and this was accompanied by cleavage of PARP, a known caspase-3 substrate. Previous studies have suggested that a caspase-3 may be the potential key enzyme that mediates HDAC inhibitor induced apoptosis (Schepper et al, 2003;Shao et al, 2004). Additionally, we found that apicidin decreased the expression of Bcl-2, an event that may disrupt mitochondrial membrane permeability and modulate the cytochrome c release.…”

Abrogation of p21 Expression by Flavopiridol Enhances Depsipeptide-Mediated Apoptosis in Malignant Pleural Mesothelioma Cells

“…In addition, FLA inhibits phosphorylation of survivin, which is required to maintain expression of this antiapoptotic protein in cancer cells (45); inhibition of p34 cdc2 kinase activity decreases survivin levels and dramatically enhances chemotherapy-induced cytotoxicity in vivo (45). Furthermore, apoptosis mediated by the novel HDAC inhibitor, chlamydocin, coincides with proteosome-mediated degradation of survivin in cancer cells (46). Although not formally demonstrated in our experiments, it is quite likely that disruption of p21/procaspase 3 complex formation contributes to potentiation of DP-mediated cytotoxicity by FLA in mesothelioma cells.…”