title: STAT3-driven transcription depends upon the dimethylation of K49 by EZH2.
abstract: Several transcription factors, including p53, NF-κB, and STAT3, are modified by the same enzymes that also modify histones, with important functional consequences. We have identified a previously unrecognized dimethylation of K49 of STAT3 that is crucial for the expression of many IL-6-dependent genes, catalyzed by the histone-modifying enzyme enhancer of zeste homolog 2 (EZH2). Loss of EZH2 is protumorigenic in leukemias, but its overexpression is protumorigenic in solid cancers. Connecting EZH2 to a functionally important methylation of STAT3, which is constitutively activated in many tumors, may help reveal the basis of the opposing roles of EZH2 in liquid and solid tumors and also may identify novel therapeutic opportunities.
authors.affiliation: Department of Molecular Genetics and.
authors.forename: Maupali
authors.initials: M
authors.lastname: Dasgupta
authors.affiliation: Department of Molecular Genetics and starkg@ccf.org.
authors.forename: Josephine Kam Tai
authors.initials: JK
authors.lastname: Dermawan
authors.affiliation: Proteomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Department of Molecular Genetics and starkg@ccf.org.
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012190:Retroviridae / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D008239:Lysine
keywords: gene expression; histone methyltransferase; posttranslational modification