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首页> 外文期刊>Molecular and Cellular Biology >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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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

机译：组蛋白去乙酰化酶抑制剂诱导的RelA / p65乙酰化和NF-κB激活的阻断通过氧化损伤，XIAP下调和c-Jun N端激酶1激活介导的过程增强了白血病细胞的凋亡。

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NF-κB activation is reciprocally regulated by RelA/p65 acetylation and deacetylation, which are mediated by histone acetyltransferases (HATs) and deacetylases (HDACs). Here we demonstrate that in leukemia cells, NF-κB activation by the HDAC inhibitors (HDACIs) MS-275 and suberoylanilide hydroxamic acid was associated with hyperacetylation and nuclear translocation of RelA/p65. The latter events, as well as the association of RelA/p65 with IκBα, were strikingly diminished by either coadministration of the IκBα phosphorylation inhibitor Bay 11-7082 (Bay) or transfection with an IκBα superrepressor. Inhibition of NF-κB 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-Jun 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-κB inactivation and ROS generation. Finally, XIAP overexpression dramatically protected cells against the Bay/HDACI regimen but failed to prevent ROS production and JNK1 activation. Together, these data suggest that HDACIs promote the accumulation of acetylated RelA/p65 in the nucleus, leading to NF-κB 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-κB-dependent antiapoptotic proteins, and stress-related JNK1 activation.
机译：NF-κB的激活受RelA / p65乙酰化和脱乙酰化的调控，后者由组蛋白乙酰转移酶（HATs）和脱乙酰基酶（HDAC）介导。在这里，我们证明在白血病细胞中，HDAC抑制剂（HDACIs）MS-275和辛二酰苯胺基异羟肟酸对NF-κB的激活与RelA / p65的过度乙酰化和核易位有关。通过共同施用IκBα磷酸化抑制剂Bay 11-7082（Bay）或与IκBα超阻遏物转染，可显着减少后一事件以及RelA / p65与IκBα的关联。药理抑制剂或遗传策略对NF-κB的抑制作用显着增强了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的下调以及c-Jun N端激酶1 （JNK1）激活。相反， N -乙酰基l-半胱氨酸可通过消除ROS的产生来阻断Bay / HDACIs诱导的凋亡。 JNK1激活的抑制作用减弱了Bay / HDACI的致死性，而不会影响NF-κB的失活和ROS的产生。最后，XIAP过表达极大地保护了细胞免受Bay / HDACI方案的侵害，但未能阻止ROS的产生和JNK1的激活。总之，这些数据表明，HDACIs促进了乙酰化RelA / p65在细胞核中的积累，从而导致NF-κB活化。此外，通过药理或遗传手段对这些事件的干扰会导致HDACI介导的致死性显着增加，其原因是氧化损伤增强，NF-κB依赖性抗凋亡蛋白下调以及应激相关的JNK1活化。

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