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CELLULAR AND MOLECULAR

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

Department of Biochemistry, University of Antwerp, Antwerp, Belgium (S.D.S.); Department of Oncology Discovery Research, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium (H.B., T.V., U.S., W.W., M.J., J.A., J.V.h.); and HistogeneX N.V., Edegem, Belgium (L.A.)

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 IC₅₀ 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 G₂/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.

Address correspondence to: Stefanie H. De Schepper, Oncology Discovery Research, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. E-mail: sdschepp{at}prdbe.jnj.com

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