A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity.
Histone deacetylase (HDAC) inhibitors perturb the cell cycle and have great potential as anti-cancer agents, but their mechanism of action is not well established. HDACs classically function as repressors of gene expression, tethered to sequence-specific transcription factors. Here we report that HDAC3 is a critical, transcription-independent regulator of mitosis. HDAC3 forms a complex with A-Kinase-Anchoring Proteins AKAP95 and HA95, which are targeted to mitotic chromosomes. Deacetylation of H3 in mitosis requires AKAP95/HA95 and HDAC3 and provides a hypoacetylated H3 tail that is the preferred substrate for Aurora B kinase. Phosphorylation of H3S10 by Aurora B leads to dissociation of HP1 proteins from methylated H3K9 residues on mitotic heterochromatin. This transcription-independent pathway, involving interdependent changes in histone modification and protein association, is required for normal progression through mitosis and is an unexpected target of HDAC inhibitors, a class of drugs currently in clinical trials for treating cancer.
Li
Yun
Y
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Kao
Gary D
GD
Garcia
Benjamin A
BA
Shabanowitz
Jeffrey
J
Hunt
Donald F
DF
Qin
Jun
J
Phelan
Caroline
C
Lazar
Mitchell A
MA
D054758:A Kinase Anchor Proteins; D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012313:RNA / Q000235:genetics; D034622:RNA Interference; D000099186:Histone Deacetylase 3
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D064107:Aurora Kinase B; D064127:Aurora Kinases; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D000099186:Histone Deacetylase 3; C485099:AKAP8 protein, human; C012589:trichostatin A; C576921:AURKB protein, human