Deregulation of NR2E3, an orphan nuclear receptor, by benzo(a)pyrene-induced oxidative stress is associated with histone modification status change of the estrogen receptor gene promoter.
Deregulation of NR2E3, an orphan nuclear receptor, by benzo(a)pyrene-induced oxidative stress is associated with histone modification status change of the estrogen receptor gene promoter.
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DOI：
10.1016/j.toxlet.2015.06.1708
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发表时间：
2015-09-17
影响因子：
3.5
通讯作者：
Kim K
中科院分区：
文献类型：
--
作者：
Khanal T;Kim D;Johnson A;Choubey D;Kim K
我们以前报道过，NR 2 E3是一种孤儿核受体，在维持雌激素受体α（ER）的基础表达方面起着重要作用，并且NR 2 E3水平与乳腺癌患者的无复发生存率高度相关。在这里，我们研究了NR 2 E3在苯并（a）芘（BaP）介导的细胞损伤中的作用。BaP处理减少NR 2 E3同源二聚体的形成和表达，随后降低ER表达。染色质免疫沉淀分析结果表明，用BaP处理MCF-7乳腺癌细胞和小鼠肝脏，从ER启动子释放NR 2 E3，将转录活性组蛋白修饰状态转化为抑制状态。MCF-7细胞中NR 2 E3的缺失也诱导了ER启动子区类似的非活性表观遗传状态，表明NR 2 E3是维持基础ER表达的重要表观遗传参与者。有趣的是，BaP对NR 2 E3和ER表达水平的这些负面影响被抗氧化剂治疗所挽救。总的来说，我们的研究提供了新的证据，表明BaP诱导的氧化应激降低ER表达，部分通过调节NR 2 E3功能，调节ER启动子的表观遗传状态。NR 2 E3可能是维持基础ER表达以保护细胞免受BaP诱导的氧化损伤的重要表观遗传参与者。
We previously reported that NR2E3, an orphan nuclear receptor, plays an important role in maintaining the basal expression of estrogen receptor α (ER) and that the NR2E3 level is highly correlated with the relapse-free survival of breast cancer patients. Here, we investigated the role of NR2E3 in benzo(a)pyrene (BaP)-mediated cell injury. BaP treatment reduced NR2E3 homo-dimer formation and expression and subsequently decreased ER expression. The chromatin immunoprecipitation assay results showed that the treatment of MCF-7 breast cancer cells and the mouse liver with BaP released NR2E3 from the ER promoter to transform the transcriptionally active histone modification status into a repressive state. NR2E3 depletion in MCF-7 cells also induced a similar inactive epigenetic status in the ER promoter region, indicating that NR2E3 is an essential epigenetic player that maintains basal ER expression. Interestingly, these negative effects of BaP on the expression levels of NR2E3 and ER were rescued by antioxidant treatment. Collectively, our study provides novel evidence to show that BaP-induced oxidative stress decreases ER expression, in part by regulating NR2E3 function, which modulates the epigenetic status of the ER promoter. NR2E3 is likely an essential epigenetic player that maintains basal ER expression to protect cells from BaP-induced oxidative injury.