Functional interplay between modulation of histone deacetylase activity and its regulatory role in G2-M transition

The acetylation status of histories plays an essential role in regulating transcription and replication, and is thus involved in the proliferation and differentiation of normal and neoplastic cells. Here, we investigated the effect of trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), on G2-M transition during the cell cycle. HDAC inhibition by TSA arrested the cell cycle at G2 and also induced escape from the mitotic arrest into G1. TSA reduced the expression of cyclin B1, a key cyclin for G2-M transition, but stimulated expression of p21(WAFI/Cipl), an inhibitor of CDK and Cdc2. In contrast, the expression of cyclin B1 but not p21(WAFI/Cipl) is enhanced during M. Moreover, histone acetylation at promoters of these two genes was regulated by TSA. TSA augmented acetylation of the p21(WAFI/Cipl) promoter but reduced that of the cyclin B1 promoter, suggesting the relationship between TSA-induced modulation of histone acetylation and differential expression of these genes. Taken together, our observations suggest that modulation of HDAC activity is implicated in the G2-M transition by regulating the transcription of cell cycle regulators, p21(WAFI, Cipl) and cyclin B1, via modulating acetylation status of the histones at their promoters. (C) 2003 Elsevier Inc. All rights reserved.