Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies. PHYSIOLOGICAL FUNCTIONS OF EZH2 EZH2 and Polycomb complex-mediated transcription repressionEpigenetic modifications play important biological roles because they regulate gene expression by modifying chromatin organization and by modulating transcription initiation, elongation, splicing and termination. Epigenetic modifications are dynamically established by DNA methyltransferases (DNMTs) and by many categories of histone-modifying enzymes that write, read and erase histone modifications [1] in a highly regulated manner. Given the importance of epigenetic information in the control of DNA functions, epigenetic deregulations play a key role in the development of many diseases, including cancer where they have been extensively studied [2][3][4][5].EZH2, one of the most studied histone-modifying enzymes, is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). PRC2 is one of the two major classes of Polycomb complexes and is responsible for maintaining its target genes in a transcriptionally repressed state through tri-methylation of lysine 27 on histone H3 (H3K27me3) [6]. The other PRC2 members are EED, SUZ12, RBAP46/48 and AEBP2. Although their function has not been fully characterized, it is clear that EZH2 requires at least EED and SUZ12 to be catalytically active in vitro, while RBAP46/48 and AEBP2 stimulate EZH2 activity [6].It has been suggested that EZH2-mediated H3K27me3 allows Polycomb Repressive Complex 1 (PRC1) recruitment to chromatin that will then monoubiquitinylate lysine 119 of histone H2A (H2AK119ub1), thus establishing a higher repressive state of chromatin ( Figure 1) [7,8]. Alternatively, following H2AK119ub1 by alternative PRC1-like complexes, PRC2 components could be recruited. They, in turn, will drive the formation of canonical PRC1, suggesting an intimate interplay between PRC1 and PRC2 for target gene silencing [9,10]. Roles of EZH2 in normal hematopoiesisPRC1 and PRC2 play a major role in normal hematopoiesis by promoting pluripotency maintenance and self-renewal of adult stem cells [8,11]. EZH2 Oncotarget 2285 www.impactjournals.com/oncotarget involvement in hematopoiesis was first revealed by its interaction with VAV [18], an important effector in hematopoietic signal transduction [19].As EZH2,...
BackgroundMultiple myeloma (MM) is a malignant plasma cell disease with a poor survival, characterized by the accumulation of myeloma cells (MMCs) within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance.MethodsWe identified a significant upregulation of the polycomb repressive complex 2 (PRC2) core genes in MM cells in association with proliferation. We used EPZ-6438, a specific small molecule inhibitor of EZH2 methyltransferase activity, to evaluate its effects on MM cells phenotype and gene expression prolile.ResultsPRC2 targeting results in growth inhibition due to cell cycle arrest and apoptosis together with polycomb, DNA methylation, TP53, and RB1 target genes induction. Resistance to EZH2 inhibitor is mediated by DNA methylation of PRC2 target genes. We also demonstrate a synergistic effect of EPZ-6438 and lenalidomide, a conventional drug used for MM treatment, activating B cell transcription factors and tumor suppressor gene expression in concert with MYC repression. We establish a gene expression-based EZ score allowing to identify poor prognosis patients that could benefit from EZH2 inhibitor treatment.ConclusionsThese data suggest that PRC2 targeting in association with IMiDs could have a therapeutic interest in MM patients characterized by high EZ score values, reactivating B cell transcription factors, and tumor suppressor genes.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0554-4) contains supplementary material, which is available to authorized users.
Plasma cells (PCs) play a major role in the defense of the host organism against pathogens. We have shown that PC generation can be modeled using multi-step culture systems that reproduce the sequential cell differentiation occurring in vivo. Using this unique model, we investigated the role of EZH2 during PC differentiation (PCD) using H3K27me3 and EZH2 ChIP-binding profiles. We then studied the effect of the inhibition of EZH2 enzymatic activity to understand how EZH2 regulates the key functions involved in PCD. EZH2 expression significantly increases in preplasmablasts with H3K27me3 mediated repression of genes involved in B cell and plasma cell identity. EZH2 was also found to be recruited to H3K27me3-free promoters of transcriptionally active genes known to regulate cell proliferation. Inhibition the catalytic activity of EZH2 resulted in B to PC transcriptional changes associated with PC maturation induction, as well as higher immunoglobulin secretion. Altogether, our data suggest that EZH2 is involved in the maintenance of preplasmablast transitory immature proliferative state that supports their amplification.
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