A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity
- Yun Li1,
- Gary D. Kao2,
- Benjamin A. Garcia3,
- Jeffrey Shabanowitz3,
- Donald F. Hunt3,4,
- Jun Qin5,
- Caroline Phelan1, and
- Mitchell A. Lazar1,6
- 1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 2Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 3Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA;
- 4Department of Pathology, University of Virginia, Charlottesville, Virginia 22904, USA;
- 5Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
Abstract
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.
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Footnotes
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↵6 Corresponding author.
↵6 E-MAIL lazar{at}mail.med.upenn.edu; FAX (215) 898-5408.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1455006.
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- Received June 2, 2006.
- Accepted July 28, 2006.
- Copyright © 2006, Cold Spring Harbor Laboratory Press
