Lam Ulysses Tsz Fung, Chen Ee Sin
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Health System (NUHS), Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Integrative Sciences & Engineering Programme, National University of Singapore, Singapore.
Int J Biochem Cell Biol. 2022 Mar;144:106155. doi: 10.1016/j.biocel.2021.106155. Epub 2022 Jan 3.
Epigenetic dysregulation is an important contributor to carcinogenesis. This is not surprising, as chromatin-genomic DNA organized around structural histone scaffolding-serves as the template on which occurs essential nuclear processes, such as transcription, DNA replication and DNA repair. Histone H3 lysine 36 (H3K36) methyltransferases, such as the SET-domain 2 protein (SETD2), have emerged as critical tumor suppressors. Previous work on mammalian SETD2 and its counterpart in model organisms, Set2, has highlighted the role of this protein in governing genomic stability through transcriptional elongation and splicing, as well as in DNA damage response processes and cell cycle progression. A compendium of SETD2 mutations have been documented, garnered from sequenced cancer patient genome data, and these findings underscore the cancer-driving properties of SETD2 loss-of-function. In this review, we consolidate the molecular mechanisms regulated by SETD2/Set2 and discuss evidence of its dysregulation in tumorigenesis. Insight into the genetic interactions that exist between SETD2 and various canonical intracellular signaling pathways has not only empowered pharmacological intervention by taking advantage of synthetic lethality but underscores SETD2 as a druggable target for precision cancer therapy.
表观遗传失调是致癌作用的一个重要因素。这并不奇怪，因为围绕结构性组蛋白支架组织的染色质 - 基因组DNA是诸如转录、DNA复制和DNA修复等重要核过程发生的模板。组蛋白H3赖氨酸36（H3K36）甲基转移酶，如SET结构域2蛋白（SETD2），已成为关键的肿瘤抑制因子。先前关于哺乳动物SETD2及其在模式生物中的对应物Set2的研究突出了该蛋白在通过转录延伸和剪接以及在DNA损伤反应过程和细胞周期进程中维持基因组稳定性方面的作用。已记录了从癌症患者基因组测序数据中收集的一系列SETD2突变，这些发现强调了SETD2功能丧失的致癌驱动特性。在本综述中，我们整合了由SETD2 / Set2调节的分子机制，并讨论了其在肿瘤发生中失调的证据。深入了解SETD2与各种经典细胞内信号通路之间存在的遗传相互作用，不仅通过利用合成致死性增强了药物干预能力，而且强调了SETD2作为精准癌症治疗的可药物靶向靶点。
