An HDAC inhibitor, trichostatin A, induces a delay at G2/M transition, slippage of spindle checkpoint, and cell death in a transcription-dependent manner

Biochem Biophys Res Commun. 2009 Jan 16;378(3):326-31. doi: 10.1016/j.bbrc.2008.11.057. Epub 2008 Nov 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / genetics
  • Cell Cycle Proteins / genetics
  • Cell Division / drug effects
  • Cell Proliferation / drug effects*
  • Chromosome Segregation / drug effects*
  • Cyclin B / metabolism
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Enzyme Inhibitors / pharmacology*
  • G2 Phase / drug effects
  • Gene Expression Regulation
  • HeLa Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins / genetics
  • Mitosis / drug effects
  • Neoplasm Proteins / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / genetics
  • Spindle Apparatus / drug effects*
  • Survivin
  • Transcription, Genetic / drug effects

Substances

  • BIRC5 protein, human
  • CCNB1 protein, human
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Survivin
  • trichostatin A
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1