The epithelial-to-mesenchymal transition (EMT) is a complex transcriptional program induced by transforming growth factor β1 (TGF-β1). Histone lysine-specific demethylase 1 (LSD1) has been recognized as a key mediator of EMT in cancer cells, but the precise mechanism that underlies the activation and repression of EMT genes still remains elusive. Here, we characterized the early events induced by TGF-β1 during EMT initiation and establishment. TGF-β1 triggered, 30–90 min post-treatment, a nuclear oxidative wave throughout the genome, documented by confocal microscopy and mass spectrometry, mediated by LSD1. LSD1 was recruited with phosphorylated SMAD2/3 to the promoters of prototypic genes activated and repressed by TGF-β1. After 90 min, phospho-SMAD2/3 downregulation reduced the complex and LSD1 was then recruited with the newly synthesized SNAI1 and repressors, NCoR1 and HDAC3, to the promoters of TGF-β1-repressed genes such as the Wnt soluble inhibitor factor 1 gene (WIF1), a change that induced a late oxidative burst. However, TGF-β1 early (90 min) repression of transcription also required synchronous signaling by reactive oxygen species and the stress-activated kinase c-Jun N-terminal kinase. These data elucidate the early events elicited by TGF-β1 and the priming role of DNA oxidation that marks TGF-β1-induced and -repressed genes involved in the EMT.

中文翻译：

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LSD1-SMAD2 / 3靶向的DNA氧化引发TGF-β1/ EMT基因激活或抑制。

上皮-间质转化（EMT）是通过转化生长因子β1（TGF-β1）诱导的复杂转录程序。组蛋白赖氨酸特异性脱甲基酶1（LSD1）已被公认为是癌细胞中EMT的关键介体，但仍无法确定EMT基因激活和抑制的精确机制。在这里，我们表征了在EMT启动和建立过程中TGF-β1诱导的早期事件。TGF-β1处理后30-90分钟触发了整个基因组的核氧化波，共聚焦显微镜和质谱法证明了LSD1的介导作用。LSD1被磷酸化的SMAD2 / 3募集到被TGF-β1激活和抑制的原型基因的启动子。90分钟后，WIF1），此变化引起后期的氧化爆发。然而，TGF-β1早期（90分钟）的转录抑制还需要通过活性氧和应激激活的激酶c-Jun N-末端激酶进行同步信号转导。这些数据阐明了由TGF-β1引起的早期事件以及DNA氧化的引发作用，该作用标志着TGF-β1诱导和抑制了参与EMT的基因。