A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity
A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity
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DOI：
10.1101/gad.1455006
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发表时间：
2006-09-15
影响因子：
10.5
通讯作者：
Lazar, Mitchell A.
中科院分区：
文献类型：
--
作者：
Li, Yun;Kao, Gary D.;Lazar, Mitchell A.
组蛋白去乙酰化酶（HDAC）抑制剂干扰细胞周期，具有很大的潜力作为抗癌药物，但其作用机制尚未完全建立。HDAC通常作为基因表达的阻遏物起作用，与序列特异性转录因子相连。在这里，我们报告说，HDAC 3是一个关键的，转录独立的有丝分裂调节。HDAC 3与A-激酶-辅助蛋白AKAP 95和HA 95形成复合物，其靶向有丝分裂染色体。有丝分裂中H3的脱乙酰化需要AKAP 95/HA 95和HDAC 3，并提供低乙酰化的H3尾，其是Aurora B激酶的优选底物。Aurora B对H3 S10的磷酸化导致HP 1蛋白从有丝分裂异染色质上的甲基化H3 K9残基上解离。这种转录非依赖性途径涉及组蛋白修饰和蛋白质缔合的相互依赖变化，是通过有丝分裂正常进展所必需的，并且是HDAC抑制剂的意外靶点，HDAC抑制剂是目前用于治疗癌症的临床试验中的一类药物。
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.