Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway
Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway
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DOI：
10.1002/bies.201400120
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发表时间：
2014-12-01
期刊：
影响因子：
4
通讯作者：
Crespo, Piero
中科院分区：
文献类型：
--
作者：
Colon-Bolea, Paula;Crespo, Piero
赖氨酸甲基化传统上与组蛋白和表观遗传学有关。最近，赖氨酸甲基转移酶和去甲基化酶——参与非组蛋白底物的甲基化——在人类肿瘤中经常被发现不受控制。在这个领域，一项新的发现揭示了甲基转移酶SMYD3是ras驱动癌症的增强剂。SMYD3在不同类型的肿瘤中上调。smyd3介导的MAP3K2甲基化增加突变体k - ras诱导的ERK1/2激活。MAP3K2的甲基化阻止了它与磷酸酶PP2A的结合，从而阻碍了这种负调节因子对Ras-ERK1/2信号的影响，导致肺和胰腺腺癌的形成。此外，SMYD3的消耗与一种MEK抑制剂协同作用，目前正在临床试验中，以阻止ras驱动的胰腺肿瘤。这些结果强调了赖氨酸甲基化在调节与肿瘤发生相关的信号通路中的重要性，并支持开发针对不受调节的赖氨酸甲基化的药物作为抗癌治疗药物。
Lysine methylation has been traditionally associated with histones and epigenetics. Recently, lysine methyltransferases and demethylases - which are involved in methylation of non-histone substrates - have been frequently found deregulated in human tumours. In this realm, a new discovery has unveiled the methyltransferase SMYD3 as an enhancer of Ras-driven cancer. SMYD3 is up-regulated in different types of tumours. SMYD3-mediated methylation of MAP3K2 increases mutant K-Ras-induced activation of ERK1/2. Methylation of MAP3K2 prevents it from binding to the phosphatase PP2A, thereby impeding the impact of this negative regulator on Ras-ERK1/2 signals, leading to the formation of lung and pancreatic adenocarcinomas. Furthermore, depletion of SMYD3 synergises with a MEK inhibitor, currently in clinical trials, to block Ras-driven pancreatic neoplasia. These results underscore the importance of lysine methylation in the regulation of signalling pathways relevant for tumourigenesis and endorse the development of drugs targeting unregulated lysine methylation as therapeutic agents in the struggle against cancer.