Inhibition of E‐cad in mouse embryonic stem cells (mESCs) leads to a switch from LIF‐BMP to Activin/Nodal‐dependent pluripotency, consistent with transition from a naïve to primed pluripotent phenotype. We have used both genetic ablation and steric inhibition of E‐cad function in mESCs to assess alterations to phenotype using quantitative mass spectrometry analysis, network models, and functional assays. Proteomic analyses revealed that one third of detected proteins were altered in E‐cad null mESCs (Ecad−/− mESCs) compared to wild type (624 proteins were downregulated and 705 were proteins upregulated). Network pathway analysis and subsequent cellular flux assays confirmed a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, specifically through mitochondrial complex III downregulation and hypoxia inducible factor 1a target upregulation. Central to this was the transcriptional coactivator EP300. E‐cad is a well‐known tumor suppressor, its downregulation during cancer initiation and metastasis can be linked to the metabolic switch known as Warburg effect. This study highlights a phenomena found in both primed pluripotent state and cancer stemness and links it to loss of E‐cad. Data are available via ProteomeXchange with identifier PXD012679.

中文翻译：

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上皮钙粘蛋白调节小鼠胚胎干细胞初始状态和初始状态之间的转换

小鼠胚胎干细胞 (mESCs) 中 E-cad 的抑制导致从 LIF-BMP 转变为激活素/节点依赖性多能性，与从幼稚到致敏多能表型的转变一致。我们已经在 mESC 中使用了 E-cad 功能的遗传消融和空间抑制，以使用定量质谱分析、网络模型和功能分析来评估表型的改变。蛋白质组学分析显示，与野生型相比，E-cad 无效 mESC（Ecad-/- mESC）中检测到的蛋白质中有三分之一发生了改变（624 种蛋白质下调，705 种蛋白质上调）。网络通路分析和随后的细胞通量分析证实了从氧化磷酸化 (OXPHOS) 到有氧糖酵解的代谢转变，特别是通过线粒体复合物 III 下调和缺氧诱导因子 1a 目标上调。其核心是转录共激活因子 EP300。E-cad 是一种众所周知的肿瘤抑制因子，它在癌症发生和转移过程中的下调可能与称为 Warburg 效应的代谢转换有关。这项研究强调了在引发多能状态和癌症干细胞中发现的现象，并将其与 E-cad 的丢失联系起来。数据可通过 ProteomeXchange 获得，标识符为 PXD012679。这项研究强调了在引发多能状态和癌症干细胞中发现的现象，并将其与 E-cad 的丢失联系起来。数据可通过 ProteomeXchange 获得，标识符为 PXD012679。这项研究强调了在引发多能状态和癌症干细胞中发现的现象，并将其与 E-cad 的丢失联系起来。数据可通过 ProteomeXchange 获得，标识符为 PXD012679。