Inhibition of histone deacetylase activity increases chromosomal instability by the aberrant regulation of mitotic checkpoint activation

• Published in: Oncogene Vol. 22; no. 25; pp. 3853 - 3858
• Main Authors: Shin, Hyun-Jin, Baek, Kwan-Hyuck, Jeon, Ae-Hwa, Kim, So-Jung, Jang, Kyung-Lib, Sung, Young-Chul, Kim, Chang-Min, Lee, Chang-Woo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.06.2003; Nature Publishing; Nature Publishing Group
• Subjects: Acetylation; Acetylation - drug effects; Acetyltransferases - antagonists & inhibitors; Acetyltransferases - physiology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Biomarkers; Cancer; Cell Biology; Cell cycle; Cell Cycle Proteins; Cell survival; Chromatin; Chromosome Aberrations; Chromosomes; Chromosomes, Human - ultrastructure; Cyclin A - metabolism; Cyclin B - metabolism; Deacetylation; DNA biosynthesis; Enzyme Inhibitors - pharmacology; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Genes. Genome; Genomic instability; HeLa Cells - cytology; HeLa Cells - enzymology; Histone Acetyltransferases; Histone deacetylase; Histones - metabolism; Human Genetics; Humans; Hydroxamic Acids - pharmacology; Inhibitor of Apoptosis Proteins; Internal Medicine; Interphase - drug effects; Kinases; Localization; MAP Kinase Signaling System - drug effects; Medicine; Medicine & Public Health; Metaphase - drug effects; Microtubules - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - physiology; Mitosis; Mitosis - drug effects; Mitosis - physiology; Molecular and cellular biology; Molecular genetics; Nocodazole - pharmacology; Oncology; original-paper; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Polyploidy; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Processing, Post-Translational - drug effects; Protein-Serine-Threonine Kinases; Proteins - metabolism; Saccharomyces cerevisiae Proteins - antagonists & inhibitors; Saccharomyces cerevisiae Proteins - physiology; Transcription; Yeast; Instability; Regulation(control); Activation; Inhibition; Histone
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206502

Histone modification through acetylation and deacetylation is a key process in transcription, DNA replication, and chromosome segregation. During mitosis, histones are highly acetylated and chromatin is condensed. Here, we investigate the mechanistic involvement of histone deacetylase (HDAC) activity in the regulation of mitotic checkpoint activation. Inhibition of HDAC activity was found to cause the improper kinetochore localization of the mitotic checkpoint proteins, and to prolong mitotic arrest, and thus to lead to chromosomal instability due to aberrant exit from the mitotic cell cycle arrest. In addition, treatment with HDAC inhibitor attenuated the activations of p38 and ERK kinases, and increased the expression levels of cIAP-1, suggesting that the observed increased adaptation and chromosomal instability induced by inhibiting HDAC activity might be directly connected with the activations of cell survival and/or antiapoptotic signals. Moreover, the treatment of cells with mitotic defects with HDAC inhibitor increased their susceptibility to chromosomal instability. These results support the notion that HDAC activity plays an important role in the regulation of mitotic checkpoint activation, and thus the aberrant control of HDAC activity contributes to chromosomal instability.