EZH2 in Normal and Malignant Hematopoiesis

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EZH2 in Normal and Malignant Hematopoiesis Leukemia (2014) 28,44–49 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu CONCISE REVIEW EZH2 in normal and malignant hematopoiesis K Lund1, PD Adams2 and M Copland3 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. Leukemia (2014) 28, 44–49; doi:10.1038/leu.2013.288 Keywords: EZH2; hematopoiesis; cancer stem cell; lymphoma; EZH2 inhibitors INTRODUCTION EZH2 AND THE POLYCOMB GROUP COMPLEX Strictly, epigenetics is defined as a collection of heritable EZH2, a polycomb group (PcG) protein, functions in concert with mechanisms capable of altering genome function other than by other proteins (EED, SUZ12 and RBBP4), which together form the direct alteration of the DNA sequence. Here we use ‘epigenetic’ multi-subunit polycomb repressive complex (PRC)-2. PRC2 acts via more loosely to refer to elements of chromatin structure that a number of mechanisms to initiate polycomb-mediated gene control genome function, regardless of whether the control is repression (Figure 1). The mechanisms include direct inhibition of heritable. Epigenetic or chromatin-based regulation contributes to transcriptional machinery via RNA polymerase II and chromatin the control of gene expression in normal development and cancer compaction, which inhibits the access and action of transcription states. factors.9 EZH2 has also been suggested to facilitate DNA Histone proteins, which are responsible for packaging and methylation, by acting as a recruitment platform for DNA ordering DNA into the nucleosomal subunits that comprise methyltransferases.10 Importantly, following trimethylation by chromatin fibers, are frequently covalently modified at their the suppressor of variegation 3–9, enhancer of zeste and N-terminal tails. These histone ‘marks’ are defined by the histone, trithorax (SET) domain of EZH2, the histone mark H3K27me3 the modified amino acid, its position in the polypeptide chain and functions as a docking site to recruit a second polycomb complex the nature of the modification, for example, methylation or PRC1, which acts to maintain gene repression via ubiquitination of acetylation (for example, trimethylation on lysine 27 of histone H3 H2AK119.2,11 is abbreviated to H3K27me3). These marks are thought to control DNA transcription and other DNA functions, and have become known as the ‘histone code’ or perhaps, more accurately, ‘histone EZH2 FUNCTION IN STEM CELLS language’.1 EZH2 contributes to the regulation of cell fate decisions, Changes to the nucleosome structure and/or function result orchestrating gene expression to control the balance between from the activity of histone-modifying enzymes. One of the best self-renewal and differentiation.12 EZH2 has its predominant role described is the histone methyltransferase Enhancer of Zeste in embryonic development and becomes downregulated in some Homologue 2 (EZH2), responsible for trimethylating lysine 27 of adult differentiated tissues.13 However, PcG proteins also have an histone H3 to generate H3K27me3.2 This article will focus on the important role in maintaining the multi-potency of adult stem effect of mutations and other modes of dysregulation of EZH2 in cells in various contexts, including hematopoietic tissues.14 In hematological malignancy. EZH2 is one of several chromatin hematopoietic stem cell (HSC) models, at times of replicative regulatory proteins that have prompted great clinical and stress, or as cells age, the balance shifts toward differentiation with scientific interest as they offer the possibility of new therapeutic potential to ‘exhaust’ the HSC pool.15 However, Ezh2 has been targets in cancer.3–8 shown to stabilize the chromatin structure and maintain 1Department of Epigenetics of Cancer and Aging, Institute of Cancer Sciences, University of Glasgow, Cancer Research UK Beatson Labs, Glasgow, Scotland, UK; 2Department of Epigenetics of Cancer and Aging, Institute of Cancer Sciences, University of Glasgow, Beatson Institute for Cancer Research, Glasgow, Scotland, UK and 3Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow, Scotland. Correspondence: Professor M Copland, Paul O’Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow, G12 0ZD, Scotland, UK. E-mail: [email protected] Received 7 May 2013; revised 1 September 2013; accepted 20 September 2013; accepted article preview online 7 October 2013; advance online publication, 1 November 2013 EZH2 in normal and malignant hematopoiesis K Lund et al 45 RBP48 EED PRC1 PRC 2 SUZ12 EZH2 SET RING1 PH1 PC1 BMI1 H3K27 H2AK119 Me Ub MeC Figure 1. The interactions and effects of EZH2 in regulation of transcriptional repression. Polycomb complex 2 (PRC2) exerts methyltransferase activity to H3K27 via the SET domain of the EZH2 subunit. This results in transcriptional repression via various mechanisms, including the recruitment of DNA methyltransferases (DNMT) and PRC1, which ubiquitinates H2AK119. Figure 2. Regulation of EZH2 in normal and cancer states. HDAC, long-term self-renewal potential of HSCs by switching off histone deacetylase; miR, microRNA; PI3K, phosphatidylinositol 15,16 3-kinase; PTEN, phosphatase and tensin homolog. (a) Homeostatic pro-differentiation genes and promoting a shift toward relationship between c-MYC, EZH2 and the PI3K pathway in proliferation by increasing expression of genes, which facilitate 17 controlled cell growth. (b) In c-MYC driven lymphomagenesis, progression through the cell cycle. c-MYC and EZH2 contribute to each other’s upregulation via the activity of miR-26a and miR-494. EZH2 forms a co-repressor complex with HDAC3 and c-MYC to repress miR-29, which drive cancerous EZH2 AND CANCER STEM CELLS (CSCs) cell growth. The existence of the CSC, first described in the context of acute myeloid leukemia (AML),18 remains controversial, but is recognized as a viable explanation for disease propagation. The CSC hypothesis postulates that tumor tissue comprises a turn suppresses Akt. The inactivation of Akt causes an increase in heterogeneous population of cells and only a small Ezh2-mediated gene repression, including negative autoregulation subpopulation, the CSCs, has the ability to self-renew and give of c-Myc (Figure 2a).28 rise to malignant progeny. In the leukemia stem cell, EZH2 may In certain cancer states, an alteration in the relationship potentially contribute to tumorigenesis by suppressing between EZH2 and c-MYC has been observed.29 In c-MYC driven differentiation genes, thereby directing ‘healthy’ cells toward a lymphomagenesis, c-MYC and EZH2 contribute to each other’s stem cell state.19–22 This makes aberrantly expressed EZH2 an upregulation via the activity of microRNAs. c-MYC represses EZH2 attractive therapeutic target; for example, in breast and pancreatic via miR-26a and EZH2 suppresses the c-MYC-targeting miR-494 to cancer, its inhibition has the potential to deplete the CSC pool.23 maintain high levels of both proteins (Figure 2b). EZH2 forms a PcG target genes identified in embryonic stem cells (ESCs) are co-repressor complex with HDAC3 and c-MYC to repress miR-29, in more likely to be DNA hypermethylated in cancers, as shown in turn facilitating the expression of miR-29 target genes, which drive colon and embryonic carcinoma cell lines.24–26 Perhaps aggressive mantle cell lymphoma growth. Aberrant microRNA accounting for this, is evidence suggesting that EZH2 recruits expression has been shown to regulate EZH2 in other cancer DNA methyltransferases to the promoter region of PcG target contexts; for example, dysregulation of miR-101 and miR-144 is genes resulting in the silencing of PcG targets, including tumor- linked to overexpression of EZH2 in bladder and prostate cancer, suppressor genes.10 This indicates strong cross-talk between respectively.30,31 histone and DNA methylation resulting in a ‘double-lock’ repressive effect. There is further evidence to indicate that this combined epigenetic repressive effect becomes established in response to cancer-promoting
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