HDAC6 Deacetylates Ku70 and Regulates Ku70-Bax Binding in Neuroblastoma
HDAC6 Deacetylates Ku70 and Regulates Ku70-Bax Binding in Neuroblastoma
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DOI：
10.1593/neo.11558
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发表时间：
2011-08-01
期刊：
影响因子：
4.8
通讯作者：
Kwok, Roland P. S.
中科院分区：
文献类型：
--
作者：
Subramanian, Chitra;Jarzembowski, Jason A.;Kwok, Roland P. S.
Ku70首先被鉴定为在非同源末端连接DNA修复中结合DNA双链断裂的核因子。然而，最近的研究表明，Ku70也存在于细胞质中，并与Bax结合，阻止Bax诱导的细胞死亡。我们已经表明，在神经母细胞瘤细胞中，Ku70和Bax之间的结合依赖于Ku70的乙酰化状态，因此，当Ku70被乙酰化时，Bax从Ku70释放，触发细胞死亡。因此，为了生存，在神经母细胞瘤细胞中，细胞质Ku70乙酰化状态被仔细调节，使得Ku70维持在脱乙酰化状态，保持Bax与Ku70复合。我们已经表明，CREB结合蛋白（CBP），一种已知的乙酰转移酶，乙酰化Ku70，释放Bax从Ku70，引发细胞凋亡的过度表达。虽然我们已经表明，使用非类型特异性抑制剂阻断去乙酰化酶活性也会触发Ku70乙酰化和依赖性细胞死亡，但这些去乙酰化酶抑制剂在神经母细胞瘤细胞中的靶点仍然未知。在这里，我们证明，在神经母细胞瘤细胞中，组蛋白脱乙酰基酶6（HDAC6）结合Ku70和Bax在细胞质中，并敲低HDAC6或使用HDAC6特异性抑制剂触发依赖性细胞死亡。我们的研究结果表明，HDAC6调节神经母细胞瘤细胞中Ku70和Bax之间的相互作用，可能是这种儿科实体瘤的治疗靶点。
Ku70 was first characterized as a nuclear factor that binds DNA double-strand breaks in nonhomolog end-joining DNA repair. However, recent studies have shown that Ku70 is also found in the cytoplasm and binds Bax, preventing Bax-induced cell death. We have shown that, in neuroblastoma cells, the binding between Ku70 and Bax depends on the acetylation status of Ku70, such that, when Ku70 is acetylated, Bax is released from Ku70, triggering cell death. Thus, to survive, in neuroblastoma cells, cytoplasmic Ku70 acetylation status is carefully regulated such that Ku70 is maintained in a deacetylated state, keeping Bax complexed with Ku70. We have shown that overexpression of CREB-binding protein (CBP), a known acetyltransferase that acetylates Ku70, releases Bax from Ku70, triggering apoptosis. Although we have shown that blocking deacetylase activity using non-type-specific inhibitors also triggers Ku70 acetylation and Bax-dependent cell death, the targets of these deacetylase inhibitors in neuroblastoma cells remain unknown. Here, we demonstrate that, in neuroblastoma cells, histone deacetylase 6 (HDAC6) binds Ku70 and Bax in the cytoplasm and that knocking down HDAC6 or using an HDAC6-specific inhibitor triggers Bax-dependent cell death. Our results show that HDAC6 regulates the interaction between Ku70 and Bax in neuroblastoma cells and may be a therapeutic target in this pediatric solid tumor.