Histone deacetylase (
HDAC) inhibitors have attracted much interest because of their ability to arrest cell growth, induce cell differentiation, and in some cases, induce apoptosis of
cancer cells. In the present study, we have examined a new
HDAC inhibitor,
suberic bishydroxamate (SBHA), for its effect on a panel of human
melanoma cell lines. We report that it induces varying degrees of apoptosis in the
melanoma lines but not in melanocytes and fibroblasts. Induction of apoptosis was
caspase dependent and was associated with induction of changes in mitochondrial membrane permeability, which could be inhibited by overexpression of Bcl-2. The changes in mitochondria were independent of
caspase activation and were associated with changes in conformation of Bax. SBHA down-regulated several key antiapoptotic
proteins including X-linked inhibitor of apoptosis and the Bcl-2 family
proteins, Bcl-XL and Mcl-1. In contrast, it induced up-regulation of the Bcl-2 family proapoptotic
proteins, Bim, Bax, and Bak. In addition, SBHA induced relocation of the
protein Bim to mitochondria and its association with Bcl-2. De novo
protein synthesis was required for initiation of apoptosis in that the
protein synthesis inhibitor,
cycloheximide, inhibited SBHA-induced conformational changes in Bax as well as changes in mitochondrial membrane permeability and activation of
caspase-3. These results suggest that SBHA induces apoptosis by changing the balance between proapoptotic and antiapoptotic
proteins in
melanoma cells. The
protein Bim may be a key initiator of apoptosis in cells treated with SBHA.