期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 13, 页码 10064-10077出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.095208
关键词
-
资金
- National Cancer Institute [CA63753, CA93738, CA100866]
- Leukemia and Lymphoma Society of America
- Lymphoma SPORE [1P50 CA130805]
- The V Foundation for Cancer Research
- National Institutes of Health [P30CA16059]
Mechanisms underlying histone deacetylase inhibitor (HDACI)-mediated NF-kappa B 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-kappa B-dependent induction of Mn-SOD2, and ROS elimination. Interference with LBH-589-mediated NF-kappa B activation (e.g. in I kappa B 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-kappa B activation while dramatically attenuating DNA damage and cell death. In contrast, TRAF2 siRNA knockdown, targeting receptor-mediated NF-kappa B activation, blocked TNF alpha- but not HDACI-mediated NF-kappa B 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-kappa B activation, resulting in diminished Mn-SOD2 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-kappa B pathway through an ATM/NEMO/SUMOylation-dependent process involving the induction of ROS and DNA damage and suggest that blocking NF-kappa B activation via the atypical ATM/NEMO nuclear pathway can enhance HDACI antileukemic activity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据