title: Inhibition of histone deacetylase activity increases chromosomal instability by the aberrant regulation of mitotic checkpoint activation.
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.
authors.affiliation: Research Institute, National Cancer Center, Ilsan-gu, Goyang, Gyeonggi-do 411-764, Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Shin
authors.forename: Kwan-Hyuck
authors.initials: KH
authors.lastname: Baek
authors.forename: Ae-Hwa
authors.initials: AH
authors.lastname: Jeon
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kyung-Lib
authors.initials: KL
authors.lastname: Jang
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Sung
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Kim
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Lee
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D018797:Cell Cycle Proteins; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000648:ultrastructure*; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells / Q000166:cytology / Q000201:enzymology; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D007399:Interphase / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008677:Metaphase / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D004791:Enzyme Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; C012589:trichostatin A; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D011494:Protein Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015739:Nocodazole