title: The histone demethylase jumonji coordinates cellular senescence including secretion of neural stem cell-attracting cytokines.
abstract: Jumonji domain-containing protein 3 (JMJD3/KDM6B) demethylates lysine 27 on histone H3 (H3K27me3), a repressive epigenetic mark controlling chromatin organization and cellular senescence. To better understand the functional consequences of JMJD3 its expression was investigated in brain tumor cells. Querying patient expression profile databases confirmed JMJD3 overexpression in high-grade glioma. Immunochemical staining of two glioma cell lines, U251 and U87, indicated intrinsic differences in JMJD3 expression levels that were reflected in changes in cell phenotype and variations associated with cellular senescence, including senescence-associated β-galactosidase (SA-β-gal) activity and the senescence-associated secretory phenotype (SASP). Overexpressing wild-type JMJD3 (JMJD3wt) activated SASP-associated genes, enhanced SA-β-gal activity, and induced nuclear blebbing. Conversely, overexpression of a catalytically inactive dominant negative mutant JMJD3 (JMJD3mut) increased proliferation. In addition, a large number of transcripts were identified by RNA-seq as altered in JMJD3 overexpressing cells, including cancer- and inflammation-related transcripts as defined by Ingenuity Pathway Analysis. These results suggest that expression of the SASP in the context of cancer undermines normal tissue homeostasis and contributes to tumorigenesis and tumor progression. These studies are therapeutically relevant because inflammatory cytokines have been linked to homing of neural stem cells and other stem cells to tumor loci.
  
  
  CONCLUSIONS
  This glioma study brings together actions of a normal epigenetic mechanism (JMJD3 activity) with dysfunctional activation of senescence-related processes, including secretion of SASP proinflammatory cytokines and stem cell tropism toward tumors.
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Patrick M
authors: PM
authors: Perrigue
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Michael E
authors: ME
authors: Silva
authors: Bioinformatics Core Facility, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Charles D
authors: CD
authors: Warden
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Nathan L
authors: NL
authors: Feng
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Michael A
authors: MA
authors: Reid
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Daniel J
authors: DJ
authors: Mota
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Lauren P
authors: LP
authors: Joseph
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Yangzi Isabel
authors: YI
authors: Tian
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Carlotta A
authors: CA
authors: Glackin
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Margarita
authors: M
authors: Gutova
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Joseph
authors: J
authors: Najbauer
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Division of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors: Karen S
authors: KS
authors: Aboody
authors: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. mbarish@coh.org.
authors: Michael E
authors: ME
authors: Barish
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D058953:Neural Stem Cells / Q000276:immunology; D018523:Tropism
chemical_list: D016207:Cytokines; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human
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