Inhibition of histone deacetylase 3 produces mitotic defects independent of alterations in histone H3 lysine 9 acetylation and methylation

Warrener, Robyn, Chia, KeeMing, Warren, William D., Brooks, Kelly and Gabrielli, Brian (2010) Inhibition of histone deacetylase 3 produces mitotic defects independent of alterations in histone H3 lysine 9 acetylation and methylation. Molecular Pharmacology, 78 3: 384-393. doi:10.1124/mol.109.062976


Author Warrener, Robyn
Chia, KeeMing
Warren, William D.
Brooks, Kelly
Gabrielli, Brian
Title Inhibition of histone deacetylase 3 produces mitotic defects independent of alterations in histone H3 lysine 9 acetylation and methylation
Formatted title
Inhibition of Histone Deacetylase 3 Produces Mitotic Defects Independent of Alterations in Histone H3 Lysine 9 Acetylation and Methylation
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
1521-0111
Publication date 2010-09
Sub-type Article (original research)
DOI 10.1124/mol.109.062976
Volume 78
Issue 3
Start page 384
End page 393
Total pages 10
Place of publication Bethesda, MD, United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Collection year 2011
Language eng
Formatted abstract
The constitutive heterochromatin of the centromere is marked by high levels of trimethylated histone H3 lysine 9 (H3K9) and binding of the heterochromatin protein 1 (HP1), which are believed to also have an important role in mitosis. Histone deacetylase inhibitors (HDACis) are a class of anticancer agents that affect many cellular processes, including mitosis. Here we examine the mechanism by which these drugs disrupt mitosis. We have used Drosophila melanogaster embryos to demonstrate that treatment with the HDACi 100 μg/ml suberic bishydroxamic acid (IC50 12 μg/ml), conditions that induce extensive H3K9 acetylation and aberrant mitosis in mammalian cells, induced aberrant mitosis in the absence of de novo transcription. We have examined the effect of the same treatment on the levels of H3K9 modification and HP1 binding in human cancer cells and found only minor effects on H3K9 methylation and HP1 binding. Complete loss of trimethylated H3K9 or depletion of HP1α and β had no effect on mitosis, although specific depletion of histone deacetylase 3 (HDAC3) replicates the mitotic defects induced by the drugs without increasing H3K9 acetylation. These data demonstrate that H3K9 methylation and HP1 binding are not the targets responsible for HDACi-induced aberrant mitosis, but it is a consequence of selective inhibition of HDAC3. Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics.
Keyword Sister-chromatid separation
Pericentric heterochromatin
Growth-inhibition
Mammalian-cells
Cancer cells
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
UQ Diamantina Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 11 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 05 Sep 2010, 00:03:17 EST