Histone modifications affect differential regulation of TGFβ- induced NADPH oxidase 4 (NOX4) by wild-type and mutant p53.
Histone modifications affect differential regulation of TGFβ- induced NADPH oxidase 4 (NOX4) by wild-type and mutant p53.
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DOI：
10.18632/oncotarget.17892
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发表时间：
2017-07-04
期刊：
影响因子：
--
通讯作者：
Leto TL
中科院分区：
文献类型：
--
作者：
Boudreau HE;Ma WF;Korzeniowska A;Park JJ;Bhagwat MA;Leto TL
之前，我们发现野生型（WT）和突变型（mut）p53通过NADPH氧化酶-4（NOX 4）差异调节活性氧（ROS）的产生：p53-WT抑制TGFβ诱导的NOX 4、ROS和细胞迁移，而肿瘤相关mut-p53蛋白增强NOX 4表达和细胞迁移。在这里，我们扩展了我们在几种肿瘤中p53对NOX 4影响的研究结果，并研究了p53和SMAD 3对NOX 4转录调控的基础。来自癌症基因组图谱（TCGA）的原发性肿瘤的表达数据的统计分析检测到mut-p53和增加的NOX 4表达之间的相关性。此外，通过改变细胞培养模型中的p53水平，我们发现几种常见的肿瘤相关突变形式支持TGFβ/SMAD 3依赖性NOX 4表达。缺失分析揭示了两个关键SMAD 3结合元件（SBE）所需的mut-p53依赖性的NOX 4诱导，而p53-WT引起剂量依赖性的抑制NOX 4转录。ChIP分析显示SMAD 3和p53-WT或mut-p53以TGFβ依赖的方式与SBE和p53反应元件相关。有趣的是，p53-WT对NOX 4的抑制作用通过其反式激活结构域的突变或组蛋白脱乙酰酶（HDAC）抑制剂处理而减轻。p300是一种转录辅助调节因子和组蛋白乙酰转移酶（HAT），其过表达增强了p53介导的NOX 4诱导，而HAT失活的p300则降低了NOX 4的表达。Mut-p53增强了NOX 4启动子内TGFβ刺激的组蛋白乙酰化。最后，伤口分析表明，NOX 4和p300促进TGFβ/mut-p53介导的细胞迁移。我们的研究为TGFβ/SMAD 3和mut-p53介导的NOX 4诱导提供了新的见解，涉及肿瘤细胞迁移中NOX 4的表观遗传控制，表明NOX 4是对抗肿瘤进展和转移的潜在治疗靶点。
Previously, we showed wild-type (WT) and mutant (mut) p53 differentially regulate reactive oxygen species (ROS) generation by NADPH oxidase-4 (NOX4): p53-WT suppresses TGFβ-induced NOX4, ROS and cell migration, whereas tumor-associated mut-p53 proteins enhance NOX4 expression and cell migration. Here, we extended our findings on the effects of p53 on NOX4 in several tumors and examined the basis of NOX4 transcriptional regulation by p53 and SMAD3. Statistical analysis of expression data from primary tumors available from The Cancer Genome Atlas (TCGA) detected correlations between mut-p53 and increased NOX4 expression. Furthermore, by altering p53 levels in cell culture models we showed several common tumor-associated mutant forms support TGFβ/SMAD3-dependent NOX4 expression. Deletion analysis revealed two critical SMAD3 binding elements (SBE) required for mut-p53-dependent NOX4 induction, whereas p53-WT caused dose-dependent suppression of NOX4 transcription. ChIP analysis revealed SMAD3 and p53-WT or mut-p53 associate with SBEs and p53 response elements in a TGFβ-dependent manner. Interestingly, the repressive effects of p53-WT on NOX4 were relieved by mutation of its transactivation domain or histone deacetylase (HDAC) inhibitor treatment. Overexpression of p300, a transcriptional co-regulator and histone acetyltransferase (HAT), enhanced p53-mediated NOX4 induction, whereas HAT-inactive p300 reduced NOX4 expression. Mut-p53 augmented TGFβ-stimulated histone acetylation within the NOX4 promoter. Finally, wound assays demonstrated NOX4 and p300 promote TGFβ/mut-p53-mediated cell migration. Our studies provide new insight into TGFβ/SMAD3 and mut-p53-mediated NOX4 induction involving epigenetic control of NOX4 in tumor cell migration, suggesting NOX4 is a potential therapeutic target to combat tumor progression and metastasis.
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