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

The online version of this article has a Supplementary Appendix. BackgroundEnhancer 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 MethodsIn 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. ResultsSignificantly higher levels of Enhancr 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 ConclusionsThese 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.Key words: adult T-cell leukemia/lymphoma, human T-cell leukemia virus type-1, Enhancer of zeste homolog 2, H3K27me3. 2011;96(4):712-719. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, Mano H, Marquez VE, Hayashi T, Yanagihara K, Moriwaki Y, Miyazaki Y, Kamihira S, and Yamada Y. 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 HaematologicaOverexpression 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

3-Deazaneplanocin A is a Promising Therapeutic Agent for Ovarian Cancer Cells

“…Our data are in agreement with previous reports demonstrating that DZNep treatment could inhibit the proliferation of many cell types (Tan et al, 2007;Sasaki et al, 2011).…”

Au cœur d’une complexité biologique

“…Sa surexpression augmente en effet le potentiel prolifératif et l'auto-renouvellement des cellules dans les maladies lymphoprolifératives T et B [30,31]. Des mutations affectant la tyrosine en position 641 du domaine catalytique de la protéine (domaine SET, suppressor of variegation 3-9, enhancer of zeste and trithorax) ont été décrites dans 7,2 % des cas de lymphomes folliculaires et dans 21,7 % des cas de lymphomes diffus à grandes cellules B [32].…”

Aspects moléculaires des lymphomes T périphériques (2)

“…La protéine HBZ bloque la transcription virale médiée par des inhibiteurs de gamma sécrétases réduit la proliféra-tion tumorale dans des modèles de xénogreffes [79]. [85,86]. En particulier, la surexpression d'EZH2 est responsable de la répression du microARN mirR-31, ce qui entraîne l'activation de la voie alternative de NF B [86].…”