Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Epigenetics Chromatin. 2019 Feb 8;12(1):11. doi: 10.1186/s13072-019-0256-y.
Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer propagation. It can be orchestrated by the activation of multiple signaling pathways, which have been found to be highly coordinated with many epigenetic regulators. Although the mechanism of EMT has been studied over decades, cross talk between signaling and epigenetic regulation is not fully understood.
Here, we present a time-resolved multi-omics strategy, which featured the identification of the correlation between protein changes (proteome), signaling pathways (phosphoproteome) and chromatin modulation (histone modifications) dynamics during TGF-β-induced EMT. Our data revealed that Erk signaling was activated in 5-min stimulation and structural proteins involved in cytoskeleton rearrangement were regulated after 1-day treatment, constituting a detailed map of systematic changes. The comprehensive profiling of histone post-translational modifications identified H3K27me3 as the most significantly up-regulated mark. We thus speculated and confirmed that a combined inhibition of Erk signaling and Ezh2 (H3K27me3 methyltransferase) was more effective in blocking EMT progress than individual inhibitions.
In summary, our data provided a more detailed map of cross talk between signaling pathway and chromatin regulation comparing to previous EMT studies. Our findings point to a promising therapeutic strategy for EMT-related diseases by combining Erk inhibitor (singling pathway) and Ezh2 inhibitor (epigenetic regulation).
上皮间质转化（EMT）在癌症传播中起着至关重要的作用。它可以通过多种信号通路的激活来协调，这些信号通路已被发现与许多表观遗传调节剂高度协调。尽管 EMT 的机制已经研究了几十年，但信号和表观遗传调控之间的串扰仍未完全理解。
在这里，我们提出了一种时间分辨的多组学策略，该策略的特点是在 TGF-β诱导的 EMT 过程中鉴定蛋白质变化（蛋白质组）、信号通路（磷酸蛋白质组）和染色质调节（组蛋白修饰）动力学之间的相关性。我们的数据显示，Erk 信号在 5 分钟的刺激中被激活，参与细胞骨架重排的结构蛋白在 1 天的处理后被调节，构成了系统变化的详细图谱。组蛋白翻译后修饰的综合分析确定 H3K27me3 为上调最显著的标记。因此，我们推测并证实，Erk 信号和 Ezh2（H3K27me3 甲基转移酶）的联合抑制比单独抑制更能有效地阻断 EMT 进展。
总之，与以前的 EMT 研究相比，我们的数据提供了信号通路和染色质调控之间相互作用的更详细图谱。我们的研究结果表明，通过结合 Erk 抑制剂（单一途径）和 Ezh2 抑制剂（表观遗传调控），为 EMT 相关疾病提供了一种有前途的治疗策略。
