文章：

泛素连接酶在致癌转化和癌症治疗中的作用

Ubiquitin ligases in oncogenic transformation and cancer therapy

原文发布日期：2017-12-15

DOI: 10.1038/nrc.2017.105

类型: Review Article

开放获取: 否

要点：

1. Ubiquitin ligases (E3s) are deregulated in cancer through diverse mechanisms, resulting in altered expression and/or activity of their target proteins.
2. Deregulated E3s contribute to uncontrolled proliferation and genomic instability that drive malignant transformation, tumour progression and therapy resistance.
3. E3s regulate major growth-promoting pathways, including those targeted by current anticancer therapies such as the MAPK or PI3K–AKT–mTOR pathways.
4. By modulating the cellular response to stress, E3s orchestrate a balance between cell growth and survival signals, which control tumour initiation and progression.
5. Cancer-associated E3s affect transcription by modulating the abundance and activity of transcriptional activators, the binding of transcriptional activators to DNA and the formation of transcriptional complexes at genes and by regulating chromatin structure.
6. E3s are important regulators of mitochondrial and receptor-mediated apoptotic and necroptotic pathways; deregulation of these pathways confers a survival advantage to cancer cells.
7. Targeting E3s is one of the more challenging areas in drug development. Increasing our understanding of their structures (that is, their crystal structures) on their own or as part of E3 complexes and of the modifications that regulate the spatial and temporal activity of E3s is expected to guide the development of biologics and small-molecule inhibitors for this class of proteins.

要点翻译：

1. 泛素连接酶（E3s）在癌症中通过多种机制失调，导致其靶蛋白的表达和/或活性发生改变。
2. 失调的E3s会促使细胞增殖失控和基因组不稳定性，从而驱动恶性转化、肿瘤进展及治疗抵抗。
3. E3s调控主要促生长通路，包括当前抗癌疗法所针对的通路，如MAPK或PI3K–AKT–mTOR通路。
4. 通过调节细胞对应激的反应，E3s协调细胞生长与存活信号之间的平衡，这一平衡控制着肿瘤的发生与发展。
5. 癌症相关E3s通过以下方式影响转录：调节转录激活因子的丰度和活性、调控转录激活因子与DNA的结合、影响基因位点转录复合物的形成，以及调控染色质结构。
6. E3s是线粒体和受体介导的凋亡及坏死性凋亡通路的重要调节因子；这些通路的失调赋予癌细胞生存优势。
7. 靶向E3s是药物开发中较为挑战性的领域之一。通过加深对E3s自身及其在E3复合物中结构（即晶体结构）的理解，以及对调控E3s时空活性修饰机制的认识，有望指导针对此类蛋白质的生物制剂和小分子抑制剂的开发。

英文摘要：

The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes. Both genetic and epigenetic alterations account for the deregulation of E3s in cancer. Consequently, the stability and/or activity of E3 substrates are also altered, in some cases leading to downregulation of tumour-suppressor activities and upregulation of oncogenic activities. A better understanding of the mechanisms underlying E3 regulation and function in tumorigenesis is expected to identify novel prognostic markers and to enable the development of the next generation of anticancer therapies. This Review summarizes the oncogenic and tumour-suppressor roles of selected E3s and highlights novel opportunities for therapeutic intervention.

摘要翻译： 

细胞对外部应激信号和DNA损伤的反应依赖于泛素连接酶（E3s）的活性，这些酶调控着包括稳态、代谢和细胞周期进程在内的众多细胞过程。E3s以时空特异性的方式识别、相互作用并泛素化蛋白底物。泛素链的拓扑结构决定了底物的命运，标记它们被蛋白酶体识别降解，或改变其亚细胞定位，或组装成功能复合体。遗传和表观遗传改变共同导致E3s在癌症中的失调。因此，E3底物的稳定性和/或活性也发生改变，在某些情况下导致抑癌活性下调和致癌活性上调。更深入地理解E3在肿瘤发生中的调控和功能机制，有望发现新的预后标志物，并推动下一代抗癌疗法的开发。本综述总结了部分E3s的致癌与抑癌作用，并强调了治疗干预的新机会。

原文链接：

Ubiquitin ligases in oncogenic transformation and cancer therapy