Aberrant activity of PRC as a result

Aberrant activity of PRC2 as a result of over expressed EZH2, has been frequently seen in a wide range of human cancers including breast and prostate tumors [10]. However, leukemia-associated epigenetic aberrations are not fully understood [7]. Herein, we will overview the current knowledge of epigenetic alterations associated with PRC2, in particular EZH2 in leukemic malignancies. We also discuss on therapeutic agents targeting EZH2 and mechanisms in which microRNAs (miRNAs) control the expression of EZH2. Elucidation of these mechanisms may propose additional treatment approaches to overcome EZH2 aberration in leukemias.
PRC2: the structure, molecular and physiological functions PRC2 is a class of multimeric PcG complexes that is linked to posttranslational histone marks specially H3K27 trimethylation whereby maintains the transcription repression of its target genes [9]. EZH2 is the catalytic component and EED, SUZ12, RBAP46/48 and AEBP2 are the other members of PRC2 complex. Although their exact function has not been well characterized, it is clear that cooperative activity is needed to exert PRC2 function. EED and SUZ12 are required to retain catalytic activity of EZH2 in vitro while the other partners AEBP2 and RBAP46/48 stimulate EZH2 enzymatic activity [9]. H3K27 trimethylation of histone tails by EZH2 allows for the other major class of PcG protein PRC1 to bind to the human leukocyte elastase and then catalyze mono-ubiquitinylation of K119 of H2A (H2AK119ub1). Thus it has been proposed that PRC1 acts downstream of PRC2 conferring further suppression of target gene expression [1]. As well as ubiquitination of H2AK119, EZH1, the catalytic subunit of PRC1, harbors the activity of methyl group addition to H3K27 and maintains much more repression of PRC2 target genes [11]. In addition, PRC2-mediated gene repression involves histone deacetylation which leads to a decrease in the expression of particular genes [12]. EZH2 can physically interact with histone deacetylases (HDAC) 1 and 2 proteins and as a result, deacetylation of histones on specific residues can occur [10]. EZH2 is a regulator of the balance between self-renewal and differentiation thereby contributes to the destination of cell division [13]. EZH2 has important roles in embryonic development [14]. It has also been shown to be implicated in maintenance of long-term self-renewal capacity in hematopoietic stem cells (HSC) by turning off the expression of differentiation genes through stabilization of chromatin structure [15] and promoting cell proliferation by increasing gene expression programs related to the cell cycle progression [16]. In addition to involvement in early development, EZH2 has predominant role in various physiological processes including X chromosome inactivation, myogenesis and B cell development [11]. In lymphoid compartment, EZH2 is upregulated in proliferating cells such as germinal center B cells, circulating lymphocytes and plasmablasts, indicating its key role in controlling the cell cycle and lymphocyte division [17]. On the other hand, EZH2 is down-regulated during B-cell differentiation and maturation. During lymphopoiesis, EZH2 acts as a key component of early checkpoint mechanism in B cell development whose expression controls transition from pro-B to pre-B cell [18].
The correlation of EZH2 with myeloid leukemias Various types of gene mutations and chromosome aberrations in EZH2 gene have been described in myeloid neoplasms affecting epigenetic regulation of target genes on H3K27. In addition to homozygous nonsense or frameshift mutations, haploinsufficiency of EZH2 in cases with monosomy 7 is another event in deficient gene expression in myeloid disorders [35]. Another mechanism may be splicing failure of EZH2 pre-mRNA in patients carrying mutations in spliceosome genes. U2AF1, SF3B1 and SRSF2 are components of spliceosome machinery which are frequently mutated in MDS, primary and secondary AML and MDS/MPN leading to EZH2 loss of function similar to former mechanisms [36,37]. Inactivation of the other components of PRC2 analogous to EZH2 such as SUZ12 and EED [22,38,39] involved in gene silencing through trimethylation of H3K27 were also identified in patients with myeloid neoplasms [40,41]. However, SUZ12 and EED deletions or mutations have scarcely been detected in AML, MDS and MPN [40,42].