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Molecular Cancer Research
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Cell Cycle and Senescence

The Histone Demethylase Jumonji Coordinates Cellular Senescence Including Secretion of Neural Stem Cell–Attracting Cytokines

Patrick M. Perrigue, Michael E. Silva, Charles D. Warden, Nathan L. Feng, Michael A. Reid, Daniel J. Mota, Lauren P. Joseph, Yangzi Isabel Tian, Carlotta A. Glackin, Margarita Gutova, Joseph Najbauer, Karen S. Aboody and Michael E. Barish
Patrick M. Perrigue
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
2Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Michael E. Silva
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Charles D. Warden
3Bioinformatics Core Facility, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Nathan L. Feng
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Michael A. Reid
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
2Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Daniel J. Mota
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Lauren P. Joseph
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Yangzi Isabel Tian
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Carlotta A. Glackin
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Margarita Gutova
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Joseph Najbauer
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Karen S. Aboody
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
4Division of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Michael E. Barish
1Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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  • For correspondence: mbarish@coh.org
DOI: 10.1158/1541-7786.MCR-13-0268 Published April 2015
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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.

Implications: 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. Mol Cancer Res; 13(4); 636–50. ©2015 AACR.

This article is featured in Highlights of This Issue, p. 593

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • ↵*P.M. Perrigue and M.E. Silva share first authorship of this article.

  • ↵#J. Najbauer, K.S. Aboody, and M.E. Barish share senior authorship of this article.

  • Received May 22, 2013.
  • Revision received January 5, 2015.
  • Accepted January 12, 2015.
  • ©2015 American Association for Cancer Research.
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Molecular Cancer Research: 13 (4)
April 2015
Volume 13, Issue 4
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The Histone Demethylase Jumonji Coordinates Cellular Senescence Including Secretion of Neural Stem Cell–Attracting Cytokines
Patrick M. Perrigue, Michael E. Silva, Charles D. Warden, Nathan L. Feng, Michael A. Reid, Daniel J. Mota, Lauren P. Joseph, Yangzi Isabel Tian, Carlotta A. Glackin, Margarita Gutova, Joseph Najbauer, Karen S. Aboody and Michael E. Barish
Mol Cancer Res April 1 2015 (13) (4) 636-650; DOI: 10.1158/1541-7786.MCR-13-0268

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The Histone Demethylase Jumonji Coordinates Cellular Senescence Including Secretion of Neural Stem Cell–Attracting Cytokines
Patrick M. Perrigue, Michael E. Silva, Charles D. Warden, Nathan L. Feng, Michael A. Reid, Daniel J. Mota, Lauren P. Joseph, Yangzi Isabel Tian, Carlotta A. Glackin, Margarita Gutova, Joseph Najbauer, Karen S. Aboody and Michael E. Barish
Mol Cancer Res April 1 2015 (13) (4) 636-650; DOI: 10.1158/1541-7786.MCR-13-0268
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