组蛋白去乙酰化酶抑制剂通过 ATM/NEMO 相关途径激活人白血病细胞中的 NF-κB。
Histone deacetylase inhibitors activate NF-kappaB in human leukemia cells through an ATM/NEMO-related pathway.
机构信息
Departments of Medicine, Richmond, Virginia 23298.
Department of Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139.
出版信息
J Biol Chem. 2010 Mar 26;285(13):10064-10077. doi: 10.1074/jbc.M109.095208. Epub 2010 Jan 11.
Mechanisms underlying histone deacetylase inhibitor (HDACI)-mediated NF-kappaB activation were investigated in human leukemia cells. Exposure of U937 and other leukemia cells to LBH-589 induced reactive oxygen species (ROS) followed by single strand (XRCC1) and double strand (gamma-H2AX) DNA breaks. Notably, LBH-589 lethality was markedly attenuated by small interfering RNA (siRNA) knockdown of the DNA damage-linked histone, H1.2. LBH-589 triggered p65/RelA activation, NF-kappaB-dependent induction of Mn-SOD2, and ROS elimination. Interference with LBH-589-mediated NF-kappaB activation (e.g. in I kappaB alpha super-repressor transfected cells) diminished HDACI-mediated Mn-SOD2 induction and increased ROS accumulation, DNA damage, and apoptosis. The Mn-SOD2 mimetic TBAP (manganese(III)-tetrakis 4-benzoic acid porphyrin) prevented HDACI-induced ROS and NF-kappaB activation while dramatically attenuating DNA damage and cell death. In contrast, TRAF2 siRNA knockdown, targeting receptor-mediated NF-kappaB activation, blocked TNFalpha- but not HDACI-mediated NF-kappaB activation and lethality. Consistent with ROS-mediated DNA damage, LBH-589 exposure activated ATM (on serine 1981) and increased its association with NEMO. Significantly, siRNA NEMO or ATM knockdown blocked HDACI-mediated NF-kappaB activation, resulting in diminished MnSOD2 induction and enhanced oxidative DNA damage and cell death. In accord with the recently described DNA damage/ATM/NEMO pathway, SUMOylation site mutant NEMO (K277A or K309A) cells exposed to LBH-589 displayed diminished ATM/NEMO association, NEMO and p65/RelA nuclear localization/activation, and MnSOD2 up-regulation. These events were accompanied by increased ROS production, gamma-H2AX formation, and cell death. Together, these findings indicate that in human leukemia cells, HDACIs activate the cytoprotective NF-kappaB pathway through an ATM/NEMO/SUMOylation-dependent process involving the induction of ROS and DNA damage and suggest that blocking NF-kappaB activation via the atypical ATM/NEMO nuclear pathway can enhance HDACI antileukemic activity.
在人类白血病细胞中研究了组蛋白去乙酰化酶抑制剂（HDACI）介导的 NF-κB 激活的机制。U937 和其他白血病细胞暴露于 LBH-589 后，会产生活性氧（ROS），随后导致单链（XRCC1）和双链（γ-H2AX）DNA 断裂。值得注意的是，通过 DNA 损伤相关组蛋白 H1.2 的小干扰 RNA（siRNA）敲低，LBH-589 的致死作用明显减弱。LBH-589 触发 p65/RelA 激活、NF-κB 依赖性诱导 Mn-SOD2 和 ROS 消除。干扰 LBH-589 介导的 NF-κB 激活（例如，在 IκBα 超抑制子转染细胞中）会降低 HDACI 介导的 Mn-SOD2 诱导并增加 ROS 积累、DNA 损伤和细胞凋亡。Mn-SOD2 模拟物 TBAP（三价锰-四（4-苯甲酸）卟啉）可防止 HDACI 诱导的 ROS 和 NF-κB 激活，同时显著减轻 DNA 损伤和细胞死亡。相比之下，TRAF2 siRNA 敲低，靶向受体介导的 NF-κB 激活，阻断 TNFα-但不阻断 HDACI 介导的 NF-κB 激活和致死作用。与 ROS 介导的 DNA 损伤一致，LBH-589 暴露激活 ATM（丝氨酸 1981 位）并增加其与 NEMO 的结合。重要的是，siRNA NEMO 或 ATM 敲低阻断了 HDACI 介导的 NF-κB 激活，导致 MnSOD2 诱导减少，氧化 DNA 损伤和细胞死亡增强。与最近描述的 DNA 损伤/ATM/NEMO 途径一致，SUMOylation 位点突变 NEMO（K277A 或 K309A）细胞暴露于 LBH-589 后，显示出 ATM/NEMO 结合减少、NEMO 和 p65/RelA 核定位/激活以及 MnSOD2 上调。这些事件伴随着 ROS 产生、γ-H2AX 形成和细胞死亡的增加。综上所述，这些发现表明，在人类白血病细胞中，HDACIs 通过涉及 ROS 和 DNA 损伤诱导的 ATM/NEMO/SUMOylation 依赖性过程激活细胞保护 NF-κB 途径，并表明通过非典型 ATM/NEMO 核途径阻断 NF-κB 激活可以增强 HDACI 的抗白血病活性。
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