Histone deacetylases (HDACs), a promising target for cancer therapy, play a role in regulating cell-cycle progression. The mechanisms for HDAC inhibition-induced regulation of G(2)/M transition and mitotic progression remain to be elucidated. Herein, we report that trichostatin A (TSA), an HDAC inhibitor, induces a delay at the G(2)/M transition, chromosome missegregation and multi-nucleation. and thereby leads to cell death by promoting exit from aberrant mitosis without spindle checkpoint. These results are associated with a transcriptional modulation of key regulator genes of the cell cycle, including CyclinB1, PIk1, Survivin, and P21(WAF1/Cip1). Actinomycin D, a transcriptional inhibitor, abrogated the TSA-induced delay of G(2)/M transition and transcriptional modulation of cell-cycle regulator genes, indicating that the impact of TSA in this manner is transcription dependent. Overall, our findings indicate that TSA provides a barrier to cell-cycle progression for antiproliferation and promotes escape from mitotic catastrophe and cell death, by inhibiting an HDAC-mediated transcriptional action. (C) 2008 Elsevier Inc. All rights reserved.