An HDAC inhibitor, trichostatin A, induces a delay at G2/M transition, slippage of spindle checkpoint, and cell death in a transcription-dependent manner.
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, Plk1, 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.
Noh
Eun Joo
EJ
Department of Molecular Science and Technology, College of Natural Sciences, Ajou University, Suwon 443-749, Daejeon 305-701, Republic of Korea.
Lim
Dae-Sik
DS
Jeong
Gajin
G
Lee
Jong-Soo
JS
D017209:Apoptosis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D020090:Chromosome Segregation / Q000187:drug effects*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D005786:Gene Expression Regulation; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008938:Mitosis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D008941:Spindle Apparatus / Q000187:drug effects*; D000077022:Survivin; D014158:Transcription, Genetic / Q000187:drug effects; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000077022:Survivin; D000097869:Polo-Like Kinase 1; C107489:BIRC5 protein, human; C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; C012589:trichostatin A