Epigenetic regulation of lung cancer cell proliferation and migration by the chromatin remodeling protein BRG1
Epigenetic regulation of lung cancer cell proliferation and migration by the chromatin remodeling protein BRG1
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染色质重塑蛋白BRG1对肺癌细胞增殖和迁移的表观遗传调控
DOI：
10.1038/s41389-019-0174-7
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发表时间：
2019-11-06
期刊：
影响因子：
6.2
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Li, Zilong;Xia, Jun;Xu, Yong
恶性肺癌细胞的特征在于不受控制的增殖和迁移。异常肺癌细胞增殖和迁移是由改变的癌症转录组编程的。潜在的表观遗传机制尚不清楚。在这里，我们报告的表达水平BRG 1，染色质重塑蛋白，显着上调，在人类肺癌活检标本的恶性程度较高的等级相比，较低的等级。小干扰RNA介导的BRG 1耗竭或药物抑制抑制肺癌细胞的增殖和迁移。在肺癌细胞中，BRG 1的缺失或抑制通过下调细胞周期蛋白B1（CCNB 1）和潜伏性TGF-β结合蛋白2（LTBP 2）来实现。进一步的分析表明，BRG 1直接结合到CCNB 1启动子，通过与E2 F1相互作用激活转录以响应缺氧刺激。另一方面，BRG 1与Sp1相互作用激活LTBP 2的转录。BRG 1通过改变靶启动子上的组蛋白修饰来调控CCNB 1和LTBP 2的转录。具体而言，BRG 1募集KDM 3A，一种组蛋白H3 K9去甲基化酶，以从靶基因启动子中去除二甲基H3 K9，从而激活转录。KDM 3A敲除通过减少肺癌增殖和迁移实现了与BRG 1沉默相同的效果。有趣的是，BRG 1通过与HIF-1α形成复合物直接激活KDM 3A转录。总之，我们的数据揭示了一种新的表观遗传机制，即恶性肺癌细胞获得了更高的增殖和迁移能力。靶向BRG 1可能产生针对恶性肺癌的有效干预策略。
Malignant lung cancer cells are characterized by uncontrolled proliferation and migration. Aberrant lung cancer cell proliferation and migration are programmed by altered cancer transcriptome. The underlying epigenetic mechanism is unclear. Here we report that expression levels of BRG1, a chromatin remodeling protein, were significantly up-regulated in human lung cancer biopsy specimens of higher malignancy grades compared to those of lower grades. Small interfering RNA mediated depletion or pharmaceutical inhibition of BRG1 suppressed proliferation and migration of lung cancer cells. BRG1 depletion or inhibition was paralleled by down-regulation of cyclin B1 (CCNB1) and latent TGF-β binding protein 2 (LTBP2) in lung cancer cells. Further analysis revealed that BRG1 directly bound to the CCNB1 promoter to activate transcription in response to hypoxia stimulation by interacting with E2F1. On the other hand, BRG1 interacted with Sp1 to activate LTBP2 transcription. Mechanistically, BRG1 regulated CCNB1 and LTBP2 transcription by altering histone modifications on target promoters. Specifically, BRG1 recruited KDM3A, a histone H3K9 demethylase, to remove dimethyl H3K9 from target gene promoters thereby activating transcription. KDM3A knockdown achieved equivalent effects as BRG1 silencing by diminishing lung cancer proliferation and migration. Of interest, BRG1 directly activated KDM3A transcription by forming a complex with HIF-1α. In conclusion, our data unveil a novel epigenetic mechanism whereby malignant lung cancer cells acquired heightened ability to proliferate and migrate. Targeting BRG1 may yield effective interventional strategies against malignant lung cancers.