title: Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3.
abstract: The growth factor and cytokine regulated transcription factor STAT3 is required for the self-renewal of several stem cell types including tumor stem cells from glioblastoma. Here we show that STAT3 inhibition leads to the upregulation of the histone H3K27me2/3 demethylase Jmjd3 (KDM6B), which can reverse polycomb complex-mediated repression of tissue specific genes. STAT3 binds to the Jmjd3 promoter, suggesting that Jmjd3 is a direct target of STAT3. Overexpression of Jmjd3 slows glioblastoma stem cell growth and neurosphere formation, whereas knockdown of Jmjd3 rescues the STAT3 inhibitor-induced neurosphere formation defect. Consistent with this observation, STAT3 inhibition leads to histone H3K27 demethylation of neural differentiation genes, such as Myt1, FGF21, and GDF15. These results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells.
authors.affiliation: Graduate Program in Cell and Molecular Physiology, Sackler School of Graduate Biomedical Sciences and Dept. of Developmental,Molecular, and Chemical Biology Tufts University School of Medicine Boston, MA, United States of America.
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Sherry-Lynes
authors.affiliation: Graduate Program in Cell and Molecular Physiology, Sackler School of Graduate Biomedical Sciences and Dept. of Developmental,Molecular, and Chemical Biology Tufts University School of Medicine Boston, MA, United States of America.
authors.forename: Sejuti
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Graduate Program in Cell and Molecular Physiology, Sackler School of Graduate Biomedical Sciences and Dept. of Developmental,Molecular, and Chemical Biology Tufts University School of Medicine Boston, MA, United States of America.
authors.forename: Shreya
authors.identifier: http://orcid.org/0000-0002-1781-1542
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Graduate Program in Cell and Molecular Physiology, Sackler School of Graduate Biomedical Sciences and Dept. of Developmental,Molecular, and Chemical Biology Tufts University School of Medicine Boston, MA, United States of America.
authors.forename: Brent H
authors.identifier: http://orcid.org/0000-0002-7598-5604
authors.initials: BH
authors.lastname: Cochran
mesh_terms: D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C078341:MYT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human