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

• Published in: Haematologica (Roma) Vol. 96; no. 5; pp. 712 - 719
• Main Authors: SASAKI, Daisuke, IMAIZUMI, Yoshitaka, MORIWAKI, Yuji, MIYAZAKI, Yasushi, KAMIHIRA, Shimeru, YAMADA, Yasuaki, HASEGAWA, Hiroo, OSAKA, Akemi, TSUKASAKI, Kunihiro, YOUNG LIM CHOI, MANO, Hiroyuki, MARQUEZ, Victor E, HAYASHI, Tomayoshi, YANAGIHARA, Katsunori
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01.05.2011
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Base Sequence; Biological and medical sciences; Blotting, Western; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer of Zeste Homolog 2 Protein; Epigenomics; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Hematologic and hematopoietic diseases; Histones - metabolism; Human viral diseases; Humans; Hydroxamic Acids - pharmacology; Indoles; Infectious diseases; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemia-Lymphoma, Adult T-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lysine - metabolism; Medical sciences; Methylation - drug effects; MicroRNAs - genetics; Oligonucleotide Array Sequence Analysis; Original; Polycomb Repressive Complex 1; Polycomb Repressive Complex 2; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors - genetics; Transcription Factors - metabolism; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Deltaretrovirus; Hematology; Targeted therapy; Adult T cell leukemia lymphoma; Retroviridae; Gene overexpression; Transcription repressor; Malignant hemopathy; Non Hodgkin lymphoma; Enhancer of zeste homolog 2; Infection; Virus; Treatment; Lysine; human T-cell leukemia virus type-1; Aminoacid; Lymphoproliferative syndrome; Viral disease; Epigenetics; HTLV-I virus; Histone H3; Cancer; H3K27me3; adult T-cell leukemia/lymphoma
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2010.028605

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. 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. 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. 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.