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.

DESIGN AND 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: Daisuke Sasaki, Yoshitaka Imaizumi, Hiroo Hasegawa, Akemi Osaka, Kunihiro Tsukasaki, Young Lim Choi, Hiroyuki Mano, Victor E Marquez, Tomayoshi Hayashi, Katsunori Yanagihara, Yuji Moriwaki, Yasushi Miyazaki, Shimeru Kamihira, Yasuaki Yamada
• Journal: Haematologica (Haematologica) Vol. 96 Issue 5 Pg. 712-9 (May 2011) ISSN: 1592-8721 [Electronic] Italy
• PMID: 21228036 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Histones
• Hydroxamic Acids
• Indoles
• Intracellular Signaling Peptides and Proteins
• MIRN101 microRNA, human
• MIRN128 microRNA, human
• MicroRNAs
• RYBP protein, human
• Repressor Proteins
• Transcription Factors
• 3-deazaneplanocin
• Panobinostat
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2
• Polycomb Repressive Complex 1
• RING1 protein, human
• Lysine
• Adenosine

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Base Sequence
• Blotting, Western
• CD4-Positive T-Lymphocytes (drug effects, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA-Binding Proteins (genetics, metabolism)
• Enhancer of Zeste Homolog 2 Protein
• Epigenomics
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic
• Histones (metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Indoles
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Leukemia-Lymphoma, Adult T-Cell (genetics, metabolism, pathology)
• Lysine (metabolism)
• Methylation (drug effects)
• MicroRNAs (genetics)
• Oligonucleotide Array Sequence Analysis
• Panobinostat
• Polycomb Repressive Complex 1
• Polycomb Repressive Complex 2
• Repressor Proteins
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors (genetics, metabolism)