Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway.
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.
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Cantabria, Santander, Spain.
Paula
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Colón-Bolea
Piero
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Crespo
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000378:metabolism*; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; C482618:MAP3K2 protein, human; D054648:Protein Phosphatase 2; D016283:Proto-Oncogene Proteins p21(ras); D008239:Lysine
ERK; MAP3K2; Ras; SMYD3; cancer; lysine methylation; lysine methyltransferases