Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-κB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-jun n-terminal kinase 1 activation
Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-κB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-jun n-terminal kinase 1 activation
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DOI：
10.1128/mcb.25.13.5429-5444.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Grant, S
中科院分区：
文献类型：
--
作者：
Dai, Y;Rahmani, M;Grant, S
NF-kappa B 的激活受到 ReIA/p65 乙酰化和脱乙酰化的相互调节，而 ReIA/p65 乙酰化和脱乙酰化是由组蛋白乙酰转移酶 (HAT) 和脱乙酰酶 (HDAC) 介导的。在这里，我们证明在白血病细胞中，HDAC 抑制剂 (HDACIs) MS-275 和辛二酰苯胺异羟肟酸激活 NF-kappa B 与 ReIA/p65 的过度乙酰化和核转位相关。后一事件以及 RelA/p65 与 I kappa B α 的关联通过同时施用 I kappa B α 磷酸化抑制剂 Bay 11-7082 (Bay) 或转染 I kappa B α 超阻遏物而显着减弱。通过药理学抑制剂或遗传策略抑制 NF-κ B 显着增强 HDACIs 诱导的细胞凋亡，并伴有活性氧 (ROS) 生成增强、Mn 超氧化物歧化酶和 XIAP 下调以及 c-Jum N 末端激酶 1 (JNK1) 激活。相反，N-乙酰基 L-半胱氨酸通过消除 ROS 生成来阻断 Bay/HDACIs 诱导的细胞凋亡。抑制 JNK1 激活可减弱 Bay/HDACI 致死率，而不影响 NF-kappa B 失活和 ROS 生成。最后，XIAP 过表达显着保护细胞免受 Bay/HDACI 方案的影响，但未能阻止 ROS 产生和 JNKI 激活。总之，这些数据表明 HDACIs 促进细胞核中乙酰化 ReIA/p65 的积累，导致 NF-kappa B 激活。此外，通过药理学或遗传手段干扰这些事件，可通过增强氧化损伤、下调 NF-κ B 依赖性抗凋亡蛋白以及应激相关的 JNK1 激活，导致 HDACI 介导的致死率急剧增加。
NF-kappa B activation is reciprocally regulated by ReIA/p65 acetylation and deacetylation, which are mediated by histone acetyltransferases (HATs) and deacetylases (HDACs). Here we demonstrate that in leukemia cells, NF-kappa B activation by the HDAC inhibitors (HDACIs) MS-275 and suberoylanilide hydroxamic acid was associated with hyperacetylation and nuclear translocation of ReIA/p65. The latter events, as well as the association of RelA/p65 with I kappa B alpha, were strikingly diminished by either coadministration of the I kappa B alpha phosphorylation inhibitor Bay 11-7082 (Bay) or transfection with an I kappa B alpha superrepressor. Inhibition of NF-kappa B by pharmacological inhibitors or genetic strategies markedly potentiated apoptosis induced by HDACIs, and this was accompanied by enhanced reactive oxygen species (ROS) generation, downregulation of Mn-superoxide dismutase and XIAP, and c-Jum N-terminal kinase 1 (JNK1) activation. Conversely, N-acetyl L-cysteine blocked apoptosis induced by Bay/HDACIs by abrogating ROS generation. Inhibition of JNK1 activation attenuated Bay/HDACI lethality without affecting NF-kappa B inactivation and ROS generation. Finally, XIAP overexpression dramatically protected cells against the Bay/HDACI regimen but failed to prevent ROS production and JNKI activation. Together, these data suggest that HDACIs promote the accumulation of acetylated ReIA/p65 in the nucleus, leading to NF-kappa B activation. Moreover, interference with these events by either pharmacological or genetic means leads to a dramatic increase in HDACI-mediated lethality through enhanced oxidative damage, downregulation of NF-kappa B-dependent antiapoptotic proteins, and stress-related JNK1 activation.