title: Overexpression of Enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy.
abstract: BACKGROUND
  Enhancer of zeste homolog 2 is a component of the Polycomb repressive complex 2 that mediates chromatin-based gene silencing through trimethylation of lysine 27 on histone H3. This complex plays vital roles in the regulation of development-specific gene expression.
  
  
  METHODS
  In this study, a comparative microarray analysis of gene expression in primary adult T-cell leukemia/lymphoma samples was performed, and the results were evaluated for their oncogenic and clinical significance.
  
  
  RESULTS
  Significantly higher levels of Enhancer of zeste homolog 2 and RING1 and YY1 binding protein transcripts with enhanced levels of trimethylation of lysine 27 on histone H3 were found in adult T-cell leukemia/lymphoma cells compared with those in normal CD4(+) T cells. Furthermore, there was an inverse correlation between the expression level of Enhancer of zeste homolog 2 and that of miR-101 or miR-128a, suggesting that the altered expression of the latter miRNAs accounts for the overexpression of the former. Patients with high Enhancer of zeste homolog 2 or RING1 and YY1 binding protein transcripts had a significantly worse prognosis than those without it, indicating a possible role of these genes in the oncogenesis and progression of this disease. Indeed, adult T-cell leukemia/lymphoma cells were sensitive to a histone methylation inhibitor, 3-deazaneplanocin A. Furthermore, 3-deazaneplanocin A and histone deacetylase inhibitor panobinostat showed a synergistic effect in killing the cells.
  
  
  CONCLUSIONS
  These findings reveal that adult T-cell leukemia/lymphoma cells have deregulated Polycomb repressive complex 2 with over-expressed Enhancer of zeste homolog 2, and that there is the possibility of a new therapeutic strategy targeting histone methylation in this disease.
authors.affiliation: Department of Laboratory Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sasaki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Imaizumi
authors.forename: Hiroo
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Akemi
authors.initials: A
authors.lastname: Osaka
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Tsukasaki
authors.forename: Young Lim
authors.initials: YL
authors.lastname: Choi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Tomayoshi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Yuji
authors.initials: Y
authors.lastname: Moriwaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Shimeru
authors.initials: S
authors.lastname: Kamihira
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D057890:Epigenomics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000077767:Panobinostat; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; C534072:MIRN101 microRNA, human; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; C434957:RYBP protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; C048460:3-deazaneplanocin; D000077767:Panobinostat; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; C080355:RING1 protein, human; D008239:Lysine; D000241:Adenosine