title: Lysine methylation represses p53 activity in teratocarcinoma cancer cells.
abstract: TP53 (which encodes the p53 protein) is the most frequently mutated gene among all human cancers, whereas tumors that retain the wild-type TP53 gene often use alternative mechanisms to repress the p53 tumor-suppressive function. Testicular teratocarcinoma cells rarely contain mutations in TP53, yet the transcriptional activity of wild-type p53 is compromised, despite its high expression level. Here we report that in the teratocarcinoma cell line NTera2, p53 is subject to lysine methylation at its carboxyl terminus, which has been shown to repress p53's transcriptional activity. We show that reduction of the cognate methyltransferases reactivates p53 and promotes differentiation of the NTera2 cells. Furthermore, reconstitution of methylation-deficient p53 mutants into p53-depleted NTera2 cells results in elevated expression of p53 downstream targets and precocious loss of pluripotent gene expression compared with re-expression of wild-type p53. Our results provide evidence that lysine methylation of endogenous wild-type p53 represses its activity in cancer cells and suggest new therapeutic possibilities of targeting testicular teratocarcinoma.
authors.affiliation: Epigenetics Program, Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Epigenetics Program, Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Zhixun
authors.initials: Z
authors.lastname: Dou
authors.affiliation: Epigenetics Program, Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Sammons
authors.affiliation: The Simons Center for Systems Biology, School of Natural Sciences, Institute for Advanced Study, Princeton, NJ 08540 alevine@ias.edu bergers@upenn.edu.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Epigenetics Program, Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; alevine@ias.edu bergers@upenn.edu.
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008745:Methylation; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018243:Teratocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; C512569:SMYD2 protein, human; D008239:Lysine
keywords: cancer; methylation; p53; pluripotency; teratocarcinoma