Induction of polyploidy by histone deacetylase inhibitor: A pathway for antitumor effects

Histone deacetylase (HDAC) inhibitors can induce various transformed cells to undergo growth arrest and/or death. Suberoylanilide hydroxamic acid (SARA) is an RDAC inhibitor which is in phase I/II clinical trials and has shown antitumor activity in hematologic and solid tumors at doses well tolerated by patients. HDAC is the target for SARA, but the mechanisms of the consequent induced death of transformed cells are not completely understood. In this study, we report that SARA induced polyploidy in human colon cancer cell line HCT116 and human breast cancer cell lines, MCF-7, MDA-MB- 231, and MBA-MD-468, but not in normal human embryonic fibroblast SW-38 and normal mouse embryonic fibroblasts. The polyploid cells lost the capacity for proliferation and committed to senescence. The induction of polyploidy was more marked in HCT116 p21(WAF1) -/- or HCT116 p53 -/- cells than in wild-type HCT116. The development of senescence of SARA-induced polyploidy cells was similar in all colon cell lines. The present findings indicate that the RDAC inhibitor could exert antitumor effects by inducing polyploidy, and this effect is more marked in transformed cells with nonfunctioning p21(WAF1) or p53 genes.