E3 ubiquitin ligases in cancer stem cells: key regulators of cancer hallmarks and novel therapeutic opportunities
E3 ubiquitin ligases in cancer stem cells: key regulators of cancer hallmarks and novel therapeutic opportunities
复制标题
癌症干细胞中的 E3 泛素连接酶：癌症标志和新治疗机会的关键调节因子
DOI：
10.1007/s13402-023-00777-x
复制
发表时间：
2023
影响因子：
6.6
通讯作者：
Bin Wang
中科院分区：
文献类型：
--
作者：
Qiang Zou;Meng Liu;Kewei Liu;Yi Zhang;Brian J. North;Bin Wang
背景人类恶性肿瘤是由具有表型和功能多样性的异质性癌细胞亚群组成的。其中，一个独特的癌症干细胞（CSC）亚群既具有自我更新的能力，又具有分化的潜力，并有助于多种肿瘤特性。因此，CSC是有效癌症治疗的有希望的细胞靶点。在分子水平上，多个干细胞调控信号通路和下游转录因子的过度激活在控制CSCs的建立和维持中起关键作用。为了调节CSC的特性，这些stemness途径控制的翻译后修饰，包括，但不限于磷酸化，乙酰化，甲基化，和ubiquitination.ConclusionIn这次审查中，我们专注于E3泛素连接酶和它们的作用和机制，在调节CSC的基本标志，如自我更新，侵袭和转移，代谢重编程，免疫逃避，和治疗抗性。此外，我们讨论了新兴的治疗方法，以消除CSC通过靶向E3泛素连接酶的化学抑制剂和蛋白水解靶向嵌合体（PROTAC），目前正在开发中的发现，临床前和临床阶段。几个突出的问题，如E3泛素连接酶的异质性和CSCs的表型/功能进化的作用仍有待研究的病理和临床相关条件下。随着功能基因组学和蛋白质组学方法在单细胞、时空甚至单分子水平上的快速应用，我们预计E3泛素连接酶的更特异和精确的功能将在决定CSC特性中被描绘出来。合理的设计和适当的翻译这些机制的理解可能会导致新的治疗模式的癌症处理医学。
BackgroundHuman malignancies are composed of heterogeneous subpopulations of cancer cells with phenotypic and functional diversity. Among them, a unique subset of cancer stem cells (CSCs) has both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties. As such, CSCs are promising cellular targets for effective cancer therapy. At the molecular level, hyper-activation of multiple stemness regulatory signaling pathways and downstream transcription factors play critical roles in controlling CSCs establishment and maintenance. To regulate CSC properties, these stemness pathways are controlled by post-translational modifications including, but not limited to phosphorylation, acetylation, methylation, and ubiquitination.ConclusionIn this review, we focus on E3 ubiquitin ligases and their roles and mechanisms in regulating essential hallmarks of CSCs, such as self-renewal, invasion and metastasis, metabolic reprogramming, immune evasion, and therapeutic resistance. Moreover, we discuss emerging therapeutic approaches to eliminate CSCs through targeting E3 ubiquitin ligases by chemical inhibitors and proteolysis-targeting chimera (PROTACs) which are currently under development at the discovery, preclinical, and clinical stages. Several outstanding issues such as roles for E3 ubiquitin ligases in heterogeneity and phenotypical/functional evolution of CSCs remain to be studied under pathologically and clinically relevant conditions. With the rapid application of functional genomic and proteomic approaches at single cell, spatiotemporal, and even single molecule levels, we anticipate that more specific and precise functions of E3 ubiquitin ligases will be delineated in dictating CSC properties. Rational design and proper translation of these mechanistic understandings may lead to novel therapeutic modalities for cancer procession medicine.