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

Oncogene volume 22, pages 3853–3858 (2003)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Frank McKeon and Dr William Earnshaw for providing materials. This work was supported by POSCO (3PD0101301) and a research grant from the National Cancer Center.

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Authors and Affiliations

  1. Research Institute, National Cancer Center, Ilsan-gu, Goyang, Gyeonggi-do, 411-764, Korea

    Hyun-Jin Shin, So-Jung Kim, Chang-Min Kim & Chang-Woo Lee

  2. Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea

    Hyun-Jin Shin, Kwan-Hyuck Baek, Ae-Hwa Jeon, Young-Chul Sung & Chang-Woo Lee

  3. Department of Microbiology, Pusan National University, Pusan, 609-735, Korea

    Kyung-Lib Jang

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  1. Hyun-Jin Shin
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Correspondence to Chang-Woo Lee.

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Shin, HJ., Baek, KH., Jeon, AH. et al. Inhibition of histone deacetylase activity increases chromosomal instability by the aberrant regulation of mitotic checkpoint activation. Oncogene 22, 3853–3858 (2003). https://doi.org/10.1038/sj.onc.1206502

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