Inhibition of histone deacetylase 3 produces mitotic defects independent of alterations in histone H3 lysine 9 acetylation and methylation.
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 mug/ml suberic bishydroxamic acid (IC(50) 12 mug/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 HP1alpha and beta 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.
Warrener
Robyn
R
Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Chia
Keeming
K
Warren
William D
WD
Brooks
Kelly
K
Gabrielli
Brian
B
D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D004331:Drosophila melanogaster / Q000196:embryology / Q000378:metabolism; D004625:Embryo, Nonmammalian; D005260:Female; D006367:HeLa Cells; D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008938:Mitosis; D011499:Protein Processing, Post-Translational; D000099186:Histone Deacetylase 3
D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D008239:Lysine; D000099186:Histone Deacetylase 3; C000715594:CBX5 protein, human