EZH2: a pleiotropic protein.

EZH2 (polycomb repressive complex 2 [PRC2] subunit) is the central core component of the PRC2, a multiprotein complex that methylates lysine 27 of histone 3 (H3K27) and acts as a transcriptional repressor by silencing expression of various target genes (see figure, path 1). The PRC2 complex is involved in a number of important physiological processes, including X-chromosome inactivation, stem cell maintenance, lymphopoiesis, cell adhesion, and migration among others. Besides its “canonical” function as PRC2-dependent H3K27 methylator, EZH2 is also capable of methylating a number of nonhistone proteins, such as STAT3, thus acting as a transcriptional activator (see figure, path 2). EZH2 has been found to be mutated in various hematopoietic neoplasms, primarily germinal center B-cell–like diffuse large B-cell lymphomas and follicular lymphomas, myelodysplastic syndromes (MDSs), and myeloproliferative neoplasms (MPNs). Two different types of mutations have been observed: loss-of-function (inactivating) and gain-of-function (activating) mutations. Inactivating mutations were reported not only from MDS and MPN patients but also from those with acute T-cell leukemia. Activating heterozygous mutations which are mostly found in lymphomas predominantly affect the tyrosine residue 641 (Y641) and less frequently the alanine residues A677 and A687 of the C-terminal EZH2 SET domain. Activating EZH2mutations lead to an increased formation of trimethylated lysines (H3K27me3), thus disturbing the “histone code.” Besides mutations, unmutated EZH2 is overexpressed in several types of neoplasms, especially lymphomas. EZH2 overexpression has generally been associated with an adverse prognosis. Attempts have been made to exploit EZH2 as a therapeutic drug target. Small molecules, designed to inhibit the enzymatic activity of EZH2, showed some promising results. These compounds were, however, mainly active against EZH2 with gain-of-function mutations and had little effect in patients with unmutated EZH2. This leads to the hypothesis that there is an additional “noncanonical” oncogenic function of unmutated EZH2, independent of its methyltransferase activity. In a series of well-designed experiments, Yan and colleagues show that EZH2 also has a transcriptional activator function independent of its histone methyltransferase activity. Starting from the observation that a significant percentage of NKTL patients harbor activating mutations of JAK3, they pursued the hypothesis of a possible functional interaction between EZH2 and JAK3 in EZH2 EED RbAp46/48