SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis.
SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis.
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SIRT3过表达和过氧化氢酶的表观遗传沉默调节CLL细胞激活AXL信号轴的ROS积累。
DOI：
10.1038/s41408-021-00484-6
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发表时间：
2021-05-17
影响因子：
12.8
通讯作者：
Ghosh AK
中科院分区：
文献类型：
--
作者：
Maiti GP;Sinha S;Mahmud H;Boysen J;Mendez MT;Vesely SK;Holter-Chakrabarty J;Kay NE;Ghosh AK
线粒体代谢是慢性淋巴细胞白血病（CLL）细胞中大量ROS的关键来源。在这里，我们检测到显着较低的超氧阴离子（O2−）水平与过氧化氢（H2 O2）的积累增加CLL细胞与正常B细胞。进一步的分析表明，线粒体超氧化物歧化酶（SOD）2，将O2−转化为H2 O2，由于SIRT 3过表达导致其组成性激活，在CLL细胞中保持脱乙酰化。此外，过氧化氢酶的表达也减少了CLL细胞表明损害H2 O2转化为水和O2，这可能会导致H2 O2积累。重要的是，我们在过氧化氢酶启动子中鉴定了两个CpG岛，并发现虽然远端CpG岛（-3619至-3765）在正常B细胞和CLL细胞中保持甲基化，但仅在CLL细胞中近端CpG岛（-174至-332）中可辨别不同程度的甲基化。最后，用去甲基化剂处理CLL细胞增加过氧化氢酶mRNA水平。从功能上讲，CLL细胞中ROS的积累激活了AXL存活轴，同时上调了SIRT 3，这表明CLL细胞快速去除高活性O2-以避免其细胞毒性作用，但保持H2 O2-水平升高以促进细胞存活。因此，使用抗氧化剂消除异常激活的细胞存活途径可以是与常规药剂组合的CLL疗法中的有效干预。
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.
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