National Brain Research Centre, Manesar, Haryana, 122 052, India.
National Brain Research Centre, Manesar, Haryana, 122 052, India.
Neurochem Int. 2021 Nov;150:105189. doi: 10.1016/j.neuint.2021.105189. Epub 2021 Sep 17.
Increasing evidences suggest that the SWI/SNF chromatin remodeling complex involved in the organization of chromatin architecture via ATP hydrolysis, plays an important role in human cancer. As TCGA gene expression analyses revealed signature of enhanced oxidative stress in GBMs harbouring Brg1mutations, we examined the involvement of ATPase subunit of BRG1 in regulating oxidative stress responses in glioma. BRG1-MUT overexpressing glioma cells exhibit intrinsically higher reactive oxygen species (ROS) levels as compared to BRG1-WT. Elevated ROS generation was concomitant with decreased expression of NF-E2- related factor 2 (NRF2), superoxide dismutases (SOD-1,2) and thioredoxins (TrX-1,2). A similar change in redox regulatory genes and ROS production was observed upon siRNA-mediated knockdown of Brg1. Increased sensitivity to temozolomide was observed upon loss of BRG1-ATPase catalytic domain. These findings highlight the role of ATPase domain of BRG1 in regulating redox homeostasis and sensitivity to oxidative stressors in glioma cells. BRG1 mutation created vulnerability to elevated ROS levels can be therapeutically exploited, with ROS stressors as a promising therapeutic target for the treatment of BRG1-mutant cancers.
越来越多的证据表明，SWI/SNF 染色质重塑复合物通过 ATP 水解参与染色质结构的组织，在人类癌症中发挥着重要作用。由于 TCGA 基因表达分析显示，携带 Brg1 突变的 GBMs 存在增强的氧化应激特征，我们研究了 BRG1 中的 ATP 酶亚基在调节神经胶质瘤的氧化应激反应中的作用。与 BRG1-WT 相比，BRG1-MUT 过表达的神经胶质瘤细胞表现出内在更高的活性氧（ROS）水平。ROS 生成增加伴随着核因子 E2 相关因子 2（NRF2）、超氧化物歧化酶（SOD-1、2）和硫氧还蛋白（TrX-1、2）表达的降低。当使用 siRNA 介导的 Brg1 敲低时，观察到氧化还原调节基因和 ROS 产生的类似变化。BRG1-ATP 酶催化结构域缺失后，对替莫唑胺的敏感性增加。这些发现强调了 BRG1 的 ATP 酶结构域在调节神经胶质瘤细胞中的氧化还原平衡和对氧化应激因子的敏感性中的作用。BRG1 突变导致对高水平 ROS 的易感性，可以被治疗性利用，ROS 应激因子是治疗 BRG1 突变癌症的有前途的治疗靶点。
