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
proteasome-mediated degradation of
survivin.