EZH2 Regulates Protein Stability via Recruiting USP7 to Mediate Neuronal Gene Expression in Cancer Cells
EZH2 Regulates Protein Stability via Recruiting USP7 to Mediate Neuronal Gene Expression in Cancer Cells
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EZH2 通过招募 USP7 介导癌细胞中的神经元基因表达来调节蛋白质稳定性
DOI：
10.3389/fgene.2019.00422
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发表时间：
2019-05-03
影响因子：
3.7
通讯作者：
Cao, Ying
中科院分区：
文献类型：
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作者：
Lei, Anhua;Chen, Lu;Cao, Ying
染色质修饰因子的错误表达和改变的表观遗传修饰在肿瘤发生中起着至关重要的作用。我们以前的研究表明，抑制表观遗传修饰酶EZH2、LSD1、DNMTS和HDACs会导致不同癌细胞有丝分裂后神经元样分化。然而，它们如何调控癌细胞中的神经元分化尚不清楚。在这里，我们发现EZH2、LSD1、DNMT1和HDAC1自身形成相互作用，同时它们也与癌细胞中的SMAD蛋白和β-连环蛋白相互作用。这些酶的化学抑制会导致除HDAC1以外的蛋白质水平降低。蛋白质水平和/或酶活性的变化进一步导致神经元基因启动子染色质修饰的变化，以及神经元基因的激活。抑制神经前体细胞(NPC)中的这些酶也会导致神经元分化，类似于癌细胞。特别是，EZH2通过募集脱泛素酶USP7与LSD1、HDAC1、DNMT1、β-连环蛋白或Smad2/4相互作用并维持其稳定性。减少EZH2导致这些蛋白的泛素化和降解增强，减少LSD1、HDAC1和DNMT1与神经基因启动子的结合，并降低WNT和转化生长因子β靶基因的激活。因此，除了组蛋白甲基化的原始功能外，EZH2还维持着一系列促进肿瘤发生的蛋白质。结合其他研究，我们得出结论，这些染色质修饰因子在癌细胞中的作用方式与在神经前体/干细胞中的作用方式相同。肿瘤细胞与神经前体细胞/干细胞之间的相似性为肿瘤的发生和发展提供了本质和统一的框架，并为癌症治疗的新策略提供了建议。
Misexpression of chromatin modification factors and changed epigenetic modifications play crucial roles for tumorigenesis. Our previous studies demonstrated that inhibition of epigenetic modification enzymes EZH2, LSD1, DNMTs, and HDACs caused post-mitotic neuron-like differentiation in different cancer cells. However, how they regulate neuronal differentiation in cancer cells was unknown. Here, we show that EZH2, LSD1, DNMT1, and HDAC1 form interactions themselves, meanwhile, they also interact with SMAD proteins and β-CATENIN in cancer cells. Chemical inhibition of these enzymes leads to reduced level of proteins except HDAC1. The change in protein level and/or enzymatic activities further result in changed chromatin modifications on neuronal gene promoters, and activation of neuronal genes. Inhibition of these enzymes in neural progenitor cells (NPCs) also caused neuronal differentiation, similar to cancer cells. Particularly, EZH2 interacts with and required for the stability of LSD1, HDAC1, DNMT1, β-CATENIN, or SMAD2/4, via recruitment of deubiquitinase USP7. Reduced EZH2 leads to enhanced ubiquitination and degradation of these proteins, and decreased binding of LSD1, HDAC1, and DNMT1 to neuronal gene promoters, and lessened Wnt and TGFβ target gene activation. Hence, EZH2 sustains a series of proteins that promote tumorigenesis, in addition to its original function of histone methylation. Considering together with other studies, we conclude that these chromatin modification factors function in the same way in cancer cells as in neural progenitor/stem cells. The similarity between cancer cells and neural progenitor/stem cells provides an insight into the essence and unified framework for cancer initiation and progression, and are suggestive for novel strategies of cancer therapy.