EZH2 in normal and malignant hematopoiesis

Abstract

The histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the polycomb group complex, is vital for stem cell development, including hematopoiesis. Its primary function, to deposit the histone mark H3K27me3, promotes transcriptional repression. The activity of EZH2 influences cell fate regulation, namely the balance between self-renewal and differentiation. The contribution of aberrant EZH2 expression to tumorigenesis by directing cells toward a cancer stem cell (CSC) state is increasingly recognized. However, its role in hematological malignancies is complex. Point mutations, resulting in gain-of-function, and inactivating mutations, reported in lymphoma and leukemia, respectively, suggest that EZH2 may serve a dual purpose as an oncogene and tumor-suppressor gene. The reduction of CSC self-renewal via EZH2 inhibition offers a potentially attractive therapeutic approach to counter the aberrant activation found in lymphoma and leukemia. The discovery of small molecules that specifically inhibit EZH2 raises the exciting possibility of exploiting the oncogenic addiction of tumor cells toward this protein. However, interference with the tumor-suppressor role of wild-type EZH2 must be avoided. This review examines the role of EZH2 in normal and malignant hematopoiesis and recent developments in harnessing the therapeutic potential of EZH2 inhibition.

STAT3-driven transcription depends upon the dimethylation of K49 by EZH2

“…For this reason, these enzymes are promising targets for antitumor drugs. Both STAT3 and EZH2 have been found to be hyperactive in numerous cancers (22,32). Our present data indicate that EZH2 has an important role in IL-6-mediated, STAT3-dependent gene expression, and therefore EZH2 inhibitors are promising therapeutic targets for solid tumors.…”

“…Our present data indicate that EZH2 has an important role in IL-6-mediated, STAT3-dependent gene expression, and therefore EZH2 inhibitors are promising therapeutic targets for solid tumors. However, the loss of EZH2 expression is characteristic of myelodysplastic syndrome, myeloproliferative disorders, and acute myeloid leukemia (32,33), supporting the need to identify alternative targets in different tumor types. However, it is worthwhile considering the use of established EZH2 inhibitors to down-regulate STAT3-dependent gene expression in cancers in which EZH2 is overexpressed.…”

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

“…The gene encoding the enhancer of zeste homolog 2 (EZH2) had gain of function mutations in 7/49 (14%) DLBCL patients sequenced 48 . EZH2 is a histone methyltransferase that functions as part of the polycomb group complex, which controls the balance between self-renewal and differentiation 49 . In germinal center (GC) B cells, EZH2 appears to suppress differentiation genes and favor behavior that resembles stem cells 50 .…”

Clonagem molecular do oncogene EZH2 de leucemia mieloide crônica e perspectivas terapêuticas

“…Nesse sentido, já existem alguns inibidores de EZH2 em desenvolvimento, alguns em fase clí-nica em linfomas de células B 24,25 . Em um estudo, Xia e colaboradores (2012), ao submeter linhagens celulares de carcinoma de pulmão células não pequenas a um tratamento com silenciamento gênico de EZH2 por RNA de interferência (RNAi), observou bloqueio do crescimento celular nas fases G0 e G1, atraso da progressão do ciclo celular, efetiva inibição da proliferação celular, maior núme-ro de células apoptóticas e redução do tamanho do tumor, quando comparado a um tratamento isolado com radioterapia.…”

“…O mesmo efeito do RNAi sobre a proliferação celular foi visto em células de carcinoma mamário 22 . Ainda, a redução eficiente no crescimento de muitos tipos de células tumorais através da inibição específica de EZH2 por short hairpin RNA faz dele um alvo terapêutico atrativo para alguns tipos de câncer 24,25 . No entanto, mesmo diante do crescimento e aperfeiçoamento das técnicas biomoleculares atualmente disponíveis, muito ainda precisa ser feito antes da solidificação da terapia gênica como uma substituta as intervenções farmacológicas na LMC.…”