Functional interplay between modulation of histone deacetylase activity and its regulatory role in G2-M transition.
The acetylation status of histones 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(WAF1/Cip1), an inhibitor of CDK and Cdc2. In contrast, the expression of cyclin B1 but not p21(WAF1/Cip1) is enhanced during M. Moreover, histone acetylation at promoters of these two genes was regulated by TSA. TSA augmented acetylation of the p21(WAF1/Cip1) 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(WAF1/Cip1) and cyclin B1, via modulating acetylation status of the histones at their promoters.
Noh
Eun Joo
EJ
Research Institute, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.
Lee
Jong-Soo
JS
D002460:Cell Line; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008938:Mitosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism
C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C012589:trichostatin A; D006655:Histone Deacetylases