Histone Demethylase Jumonji D3 (JMJD3) as a Tumor Suppressor by Regulating p53 Protein Nuclear Stabilization

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.

[1]  D. Haussler,et al.  ENCODE whole-genome data in the UCSC Genome Browser: update 2012 , 2011, Nucleic Acids Res..

[2]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[3]  Obi L. Griffith,et al.  ORegAnno: an open-access community-driven resource for regulatory annotation , 2007, Nucleic Acids Res..

[4]  Mary Goldman,et al.  The UCSC Genome Browser database: update 2011 , 2010, Nucleic Acids Res..

[5]  DelindaA . Johnson,et al.  Dual transgenic reporter mice as a tool for monitoring expression of glial fibrillary acidic protein , 2009, Journal of neurochemistry.

[6]  Deric M. Park,et al.  N-CoR Pathway Targeting Induces Glioblastoma Derived Cancer Stem Cell Differentiation , 2007, Cell cycle.

[7]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[8]  Yuri Kotliarov,et al.  Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. , 2006, Cancer cell.

[9]  E. Appella,et al.  Role for 53BP1 Tudor Domain Recognition of p53 Dimethylated at Lysine 382 in DNA Damage Signaling* , 2008, Journal of Biological Chemistry.

[10]  S. Berger,et al.  Repression of p53 activity by Smyd2-mediated methylation , 2006, Nature.

[11]  C. Plass,et al.  5-Aza-2′-deoxycytidine Activates the p53/p21Waf1/Cip1 Pathway to Inhibit Cell Proliferation* , 2004, Journal of Biological Chemistry.

[12]  K. Helin,et al.  The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. , 2009, Genes & development.

[13]  S. Benchimol,et al.  Transcriptional repression mediated by the p53 tumour suppressor , 2003, Cell Death and Differentiation.

[14]  J. Uhm.  IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype , 2012 .

[15]  H. Fine,et al.  SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. , 2009, Cell stem cell.

[16]  A. Tarakhovsky,et al.  Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex , 2010, Proceedings of the National Academy of Sciences.

[17]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[18]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[19]  M. Vidal,et al.  Polycomb Limits the Neurogenic Competence of Neural Precursor Cells to Promote Astrogenic Fate Transition , 2009, Neuron.

[20]  Wei Gu,et al.  p53 post-translational modification: deregulated in tumorigenesis. , 2010, Trends in molecular medicine.

[21]  Joana M. Xavier,et al.  p53 Interaction with JMJD3 Results in Its Nuclear Distribution during Mouse Neural Stem Cell Differentiation , 2011, PloS one.

[22]  Ming Zhou,et al.  Histone H2A.Z cooperates with RNAi and heterochromatin factors to suppress antisense RNAs , 2009, Nature.

[23]  Howard Y. Chang,et al.  Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. , 2008, Genes & development.

[24]  O. Hermanson,et al.  SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron , 2007, Nature.

[25]  Luquan Wang,et al.  Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression , 2003, Oncogene.

[26]  David Haussler,et al.  ENCODE whole-genome data in the UCSC genome browser (2011 update) , 2010, Nucleic Acids Res..

[27]  T. Veenstra,et al.  Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases , 2007, Proceedings of the National Academy of Sciences.

[28]  G. Peters,et al.  Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. , 2009, Genes & development.

[29]  Danny Reinberg,et al.  Methylation-Acetylation Interplay Activates p53 in Response to DNA Damage , 2007, Molecular and Cellular Biology.

[30]  Yuri Kotliarov,et al.  Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. , 2008, Cancer cell.

[31]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[32]  Howard Y. Chang,et al.  A histone H3 lysine 27 demethylase regulates animal posterior development , 2007, Nature.

[33]  C. Allis,et al.  Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers , 2010, Nature Reviews Cancer.

[34]  J. Fawcett,et al.  An efficient method for derivation and propagation of glioblastoma cell lines that conserves the molecular profile of their original tumours , 2009, Journal of Neuroscience Methods.

[35]  Min Gyu Lee,et al.  p53 is regulated by the lysine demethylase LSD1 , 2007, Nature.

[36]  M. Esteller,et al.  Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome , 2011, Epigenetics.

[37]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[38]  Deric M. Park,et al.  The effect of a PP2A inhibitor on the nuclear receptor corepressor pathway in glioma. , 2010, Journal of neurosurgery.

[39]  O. Hermanson,et al.  N-CoR controls differentiation of neural stem cells into astrocytes , 2002, Nature.

[40]  R. Sandberg,et al.  CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing , 2011, Nature.

[41]  Bin Tean Teh,et al.  Somatic mutations of the histone H3K27 demethylase, UTX, in human cancer , 2009, Nature Genetics.

[42]  David Haussler,et al.  The UCSC genome browser database: update 2007 , 2006, Nucleic Acids Res..

[43]  Obi L. Griffith,et al.  ORegAnno: an open access database and curation system for literature-derived promoters, transcription factor binding sites and regulatory variation , 2006, Bioinform..

[44]  G. Natoli,et al.  The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene Silencing , 2007, Cell.

[45]  G. Testa.  The time of timing: How Polycomb proteins regulate neurogenesis , 2011, BioEssays : news and reviews in molecular, cellular and developmental biology.

[46]  S. Berger,et al.  IDH mutation impairs histone demethylation and results in a block to cell differentiation , 2012, Nature.

[47]  Paul Tempst,et al.  Regulation of p53 activity through lysine methylation , 2004, Nature.

[48]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.