title: Histone demethylase Jumonji D3 (JMJD3) as a tumor suppressor by regulating p53 protein nuclear stabilization.
abstract: Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate that deregulation of JMJD3 may contribute to gliomagenesis via inhibition of the p53 pathway resulting in a block to terminal differentiation.
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Chibawanye I
authors.initials: CI
authors.lastname: Ene
authors.forename: Lincoln
authors.initials: L
authors.lastname: Edwards
authors.forename: Gregory
authors.initials: G
authors.lastname: Riddick
authors.forename: Mehmet
authors.initials: M
authors.lastname: Baysan
authors.forename: Kevin
authors.initials: K
authors.lastname: Woolard
authors.forename: Svetlana
authors.initials: S
authors.lastname: Kotliarova
authors.forename: Chen
authors.initials: C
authors.lastname: Lai
authors.forename: Galina
authors.initials: G
authors.lastname: Belova
authors.forename: Maggie
authors.initials: M
authors.lastname: Cam
authors.forename: Jennifer
authors.initials: J
authors.lastname: Walling
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Holly
authors.initials: H
authors.lastname: Stevenson
authors.forename: Hong Sug
authors.initials: HS
authors.lastname: Kim
authors.forename: Keith
authors.initials: K
authors.lastname: Killian
authors.forename: Timothy
authors.initials: T
authors.lastname: Veenstra
authors.forename: Rolanda
authors.initials: R
authors.lastname: Bailey
authors.forename: Hua
authors.initials: H
authors.lastname: Song
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005909:Glioblastoma / Q000503:physiopathology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008156:Luciferases; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000502:physiology*; D055550:Protein Stability; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D006657:Histones; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human