文章：

SIRT3过表达与过氧化氢酶的表观遗传沉默调控CLL细胞中ROS蓄积，激活AXL信号轴

SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis

原文发布日期：2021-05-17

DOI: 10.1038/s41408-021-00484-6

类型: Article

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英文摘要：

Mitochondrial metabolism is the key source for abundant ROS in chronic lymphocytic leukemia (CLL) cells. Here, we detected significantly lower superoxide anion (O2−) levels with increased accumulation of hydrogen peroxide (H2O2) in CLL cells vs. normal B-cells. Further analysis indicated that mitochondrial superoxide dismutase (SOD)2, which converts O2− into H2O2 remained deacetylated in CLL cells due to SIRT3 overexpression resulting its constitutive activation. In addition, catalase expression was also reduced in CLL cells suggesting impairment of H2O2-conversion into water and O2 which may cause H2O2-accumulation. Importantly, we identified two CpG-islands in the catalase promoter and discovered that while the distal CpG-island (−3619 to −3765) remained methylated in both normal B-cells and CLL cells, variable degrees of methylation were discernible in the proximal CpG-island (−174 to −332) only in CLL cells. Finally, treatment of CLL cells with a demethylating agent increased catalase mRNA levels. Functionally, ROS accumulation in CLL cells activated the AXL survival axis while upregulated SIRT3, suggesting that CLL cells rapidly remove highly reactive O2− to avoid its cytotoxic effect but maintain increased H2O2-level to promote cell survival. Therefore, abrogation of aberrantly activated cell survival pathways using antioxidants can be an effective intervention in CLL therapy in combination with conventional agents.
 

摘要翻译： 

线粒体代谢是慢性淋巴细胞白血病（CLL）细胞中大量活性氧（ROS）的关键来源。本研究检测发现，与正常B细胞相比，CLL细胞中超氧阴离子（O₂⁻）水平显著降低，而过氧化氢（H₂O₂）积累增加。进一步分析表明，线粒体超氧化物歧化酶（SOD）2在CLL细胞中因SIRT3过表达而持续处于去乙酰化状态，从而保持其组成性活化，该酶负责将O₂⁻转化为H₂O₂。此外，CLL细胞中过氧化氢酶的表达亦降低，提示H₂O₂向水和O₂的转化过程受损，可能导致H₂O₂积累。重要的是，我们在过氧化氢酶启动子区域发现两个CpG岛：远端CpG岛（-3619至-3765）在正常B细胞和CLL细胞中均保持甲基化状态，而近端CpG岛（-174至-332）仅在CLL细胞中出现不同程度的甲基化。最终，使用去甲基化剂处理CLL细胞可提高过氧化氢酶mRNA水平。功能上，CLL细胞中的ROS积累激活了AXL生存轴，同时上调了SIRT3，这表明CLL细胞通过快速清除高反应性的O₂⁻以避免其细胞毒性效应，但维持较高的H₂O₂水平以促进细胞存活。因此，在常规治疗药物基础上联合使用抗氧化剂来阻断异常激活的细胞生存通路，可能成为CLL治疗的有效干预策略。

原文链接：

SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis