title: Human EHMT2/G9a activates p53 through methylation-independent mechanism.
abstract: p53 is a critical tumor suppressor in humans. It functions mostly as a transcriptional factor and its activity is regulated by numerous post-translational modifications. Among different covalent modifications found on p53 the most controversial one is lysine methylation. We found that human G9a (hG9a) unlike its mouse orthologue (mG9a) potently stimulated p53 transcriptional activity. Both ectopic and endogenous hG9a augmented p53-dependent transcription of pro-apoptotic genes, including Bax and Puma, resulting in enhanced apoptosis and reduced colony formation. Significantly, shRNA-mediated knockdown of hG9a attenuated p53-dependent activation of Puma. On the molecular level, hG9a interacted with histone acetyltransferase, p300/CBP, resulting in increased histone acetylation at the promoter of Puma. The bioinformatics data substantiated our findings showing that positive correlation between G9a and p53 expression is associated with better survival of lung cancer patients. Collectively, this study demonstrates that depending on the cellular and organismal context, orthologous proteins may exert both overlapping and opposing functions. Furthermore, this finding has important ramifications on the use of G9a inhibitors in combination with genotoxic drugs to treat p53-positive tumors.
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Rada
authors.affiliation: Institute of Cytology, Saint-Petersburg, Russia.
authors.forename: E
authors.initials: E
authors.lastname: Vasileva
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.|Institute of Cytology, Saint-Petersburg, Russia.
authors.forename: L
authors.initials: L
authors.lastname: Lezina
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: D
authors.initials: D
authors.lastname: Marouco
authors.affiliation: Institute of Cytology, Saint-Petersburg, Russia.|MRC Toxicology Unit, Leicester, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Antonov
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Macip
authors.affiliation: MRC Toxicology Unit, Leicester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.affiliation: Institute of Cytology, Saint-Petersburg, Russia.
authors.forename: N A
authors.initials: NA
authors.lastname: Barlev
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015996:Survival Rate; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D014408:Biomarkers, Tumor; D006649:Histocompatibility Antigens; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human