Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications
© Ciarapica et al; licensee BioMed Central Ltd. 2011
Received: 2 February 2011
Accepted: 25 May 2011
Published: 25 May 2011
Soft tissue sarcomas of childhood are a group of heterogeneous tumors thought to be derived from mesenchymal stem cells. Surgical resection is effective only in about 50% of cases and resistance to conventional chemotherapy is often responsible for treatment failure. Therefore, investigations on novel therapeutic targets are of fundamental importance. Deregulation of epigenetic mechanisms underlying chromatin modifications during stem cell differentiation has been suggested to contribute to soft tissue sarcoma pathogenesis. One of the main elements in this scenario is enhancer of zeste homolog 2 (EZH2), a methyltransferase belonging to the Polycomb group proteins. EZH2 catalyzes histone H3 methylation on gene promoters, thus repressing genes that induce stem cell differentiation to maintain an embryonic stem cell signature. EZH2 deregulated expression/function in soft tissue sarcomas has been recently reported. In this review, an overview of the recently reported functions of EZH2 in soft tissue sarcomas is given and the hypothesis that its expression might be involved in soft tissue sarcomagenesis is discussed. Finally, the therapeutic potential of epigenetic therapies modulating EZH2-mediated gene repression is considered.
KeywordsEZH2 soft tissue sarcomas epigenetics methylation methyltransferases
Soft tissue sarcomas: a clinical challenge
Targeted therapy clinical studies for soft tissue sarcoma (STS)
Biological molecular agents
Clinical studies (phase) and clinical efficiency
Tyrosine kinase inhibitors (TKIs)
Imatinib mesylate (IM)
Phase II study: 53.7% of patients with GISTs showed a partial response, 27.9% of patients showed stable disease, 13.6% of patients showed early resistance to imatinib, 5% of patients showed serious adverse events
Phase III study: confirmation of the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST. No advantages to higher dose treatment were reported.
Sunitinib malate (SM)
VEGF-R1, VEGF-R2, VEGF-R3, c-Kit, PDGFR, Flt-3, CSF1, neurotrophic factor receptors
Phase III study: 7% of patients with GIST showed partial response, 58% had stable disease, 19% had progressive disease; 27.3 weeks was the time-to-tumor progression for sunitinib vs 6.4 weeks for placebo. Progression-free survival was similar.
Phase II study: 3-month progression-free rate of >40% for liposarcomas leiomyosarcomas
Phase II study: 52% of patients showed metabolic stable disease, 20% of patients achieved stable disease for at least 16 weeks, 47% of patients achieved partial response
Phase II study (current): SM activity in patients with certain subtypes of STS. The majority of these patients showed stable disease for 16 weeks.
VEGF-R2, VEGF-R3, c-Kit, PDGFR, Raf/Mek/Erk
Phase II study: 14% of patients with angiosarcoma and 6% of patients with leiomyosarcoma had a response, 64% of patients developed intolerance at the drug dose used
Phase II study: 78% patients with vascular tumors showed disease stabilization
Phase II study (current): antitumor activity and acceptable toxicity profile in patients with antracycline-refractory STS
Phase II study: 12-week progression-free survival was reached by 44% patients with leiomyosarcoma, 49% of patients with synovial sarcomas, and 39% of patients with the other STS types
BCR/ABL, c-Kit, PDGFR, CSF1R
Phase I study: nilotinib alone or in combination with imatinib was well tolerated and showed clinical activity in imatinib-resistant GIST patients
Mammalian target of rapamycin (mTOR) inhibitors
Phase II study: moderate toxicity and limited clinical activity
Phase II study: acceptable toxicity. Limited clinical activity in heavily pretreated patients with bone and soft tissue sarcomas. The efficacy in imatinib-refractory and sunitinib-refractory GIST is promising.
Phase I study: safety of the drug; 27% of patients showed stable disease.
Phase II study: 29% of clinical benefit rate. Prolongation of survival.
Phase III study (current)
Insulin-like growth factor (IGF) receptor antibodies
Phase I study: good tolerance of the drug
Phase II study (current): R1507 is well tolerated. Significant activity has been observed in Ewing's sarcoma, RMS and OS with several dramatic responses seen in Ewing's sarcoma and RMS.
Phase I study: absence of severe toxicities
Phase I study (current)
The Polycomb group protein EZH2 in STS
EZH2 in RMS
EZH2 in synovial sarcoma
Synovial sarcoma is a malignant cancer that affects prevalently young patients and represents almost 10% of all STSs . It is characterized by the typical translocation t(X;18)(p11;q11) that generates the fusion between the synovial sarcoma translocation, chromosome 18 (SS18 or SYT) gene on chromosome 18 and either synovial sarcoma, X breakpoint 1, 2 or 4 (SSX1, SSX2 or SSX4) genes on the X chromosome . Previously reported data showed that chimerical proteins SYT-SSX might disrupt gene expression mechanisms by functionally interacting with PcG proteins in synovial cells . In particular, SYT-SSX2 fusion protein induces downstream target-gene deregulation through epigenetic mechanisms . Recently, EZH2 has been found to mediate the effects of SYT-SSX activity. Specifically, SYT-SSX2 represses the expression of the tumor suppressor gene early growth response 1 (EGR1), a regulator of cell cycle, engaging EZH2 on the EGR1 promoter in synovial sarcoma cells (Figure 2b). EGR1 repression has been found to be associated with H3K27 trimethylation, and EZH2 and the PRC1 component BMI1 have been shown to directly bind its promoter, thus supporting the existence of a novel epigenetic mechanism of oncogenesis in synovial sarcoma . This finding illustrates how a genetic lesion that generates an oncogenic trascriptional regulator might exploit EZH2 and other epigenetic regulators to sustain tumorigenesis.
EZH2 in Ewing's sarcoma
Ewing's sarcoma is an embryonal malignancy characterized by the t(11;22)(q24;q12) translocation which generates chimerical Ewing sarcoma (EWS)/ETS fusion transcription factors. One of the most common fusion protein found in patients affected by this tumor is EWS/Friend leukemia integration 1 transcription factor (FLI1) . EZH2 is expressed at high levels in Ewing's tumors . Studying the influence of EZH2 downregulation on gene expression, Richter and colleagues found that EZH2 is responsible for the undifferentiated phenotype of Ewing's sarcoma by maintaining a stemness gene expression signature, inhibiting differentiation . Strikingly, EWS/FLI1 has been found to induce the expression of EZH2 by direct binding to its promoter in both Ewing's sarcoma cell lines and human MSCs (Figure 2c) . EWS/FLI1-dependent activation of EZH2 seems to be specific, because the other components of the PRC2/3 complex are not affected . Notably, human MSCs seem to represent a permissive environment for the expression of EWS/FLI1, which induces features in these cells that recapitulate Ewing's sarcoma biology. This observation may implicate EZH2 as a coinitiator of Ewing's sarcoma . Data from these studies offer an example of how a translocation-derived fusion product takes advantage of EZH2 recruiting this methyltransferase to drive tumor progression at the expenses of differentiation.
Concluding remarks and future perspectives
Pediatric STSs, especially those metastatic at diagnosis, are highly aggressive tumors for which there is still an unmet medical need of more effective and less toxic therapeutic approaches. The role of the epigenetic regulator EZH2 in maintaining the embryonal cell phenotype of STS, its overexpression in these cancers and its functional interaction with many fusion proteins typical of STS, suggest that EZH2 may represent both a potential marker of undifferentiated precancerous cells and a reasonable candidate therapeutic target in STS. Increasing attention is focusing on epigenetic therapies that have provided promising results in clinical trials for some human tumors [40–42]. The clinical effectiveness of epigenetic therapies in human malignancies has been recently proved by the observation that, in a randomized phase III trial, the DNA hypomethylating agent azacytidine prolonged overall survival of myelodysplastic syndrome (MDS) patients compared to other standard therapies . The potential efficacy of epigenetic therapy in STS is supported by preclinical studies employing HDAC inhibitors [36, 44–46]. Many studies on cell culture and animal models indicate that diverse epigenetic processes synergize to control gene expression. Hence, different kinds of epigenetic drugs, such as DNA-demethylating agents and HDAC inhibitors, have been included in combination treatment protocols [40, 47]. It is noteworthy that, in Ewing's sarcoma cells, HDAC inhibitor treatment in vitro induces downregulation of EZH2 , as more recently confirmed in glioma , gallbladder carcinoma  and acute myeloid leukemia . Consistently, in preclinical models of different cancers, the antitumor effect of EZH2 inhibition, obtained through the methyltransferase inhibitor 3'-deazanoplanocin (DZNep), is enhanced by addition of HDAC inhibitors [51–53]. DZNep has been shown to act by causing depletion of PRC2 subunits with subsequent reactivation of PRC2-silenced genes [54, 55]. In addition, it has been shown that the repressive function of EZH2 on gene expression is strengthened by the role of DNMTs, with which EZH2 physically interacts regulating their activity . In this view, additional usage of DNMTs inhibitors in protocols targeting EZH2 might improve response in some tumor contexts. In turn, since HMTs are also active in non-proliferating cells, the inclusion of EZH2 inhibitors in combination regimens may overcome the ineffectiveness of DNMTs inhibitors in quiescent cells. On the other hand, it must be noted that, due to the complexity of molecular crosstalk involved in epigenetic control, the use of epigenetic drugs affecting a variety of molecular networks entails the risk of unforeseeable effects. For instance, despite their antiproliferative effects in vitro, treatments employing either HDACs or DNA methylation inhibitors have been recently reported to increase in vivo the invasive capabilities of RMS cells through upregulation of the prometastatic gene Ezrin . Major questions remain open on the in vivo mechanism(s) of action of epigenetic drugs. Indeed, the clinical response to azacytidine in terms of prolongation of survival in MDS patients does not appear to be directly correlated with methylation of specific tumor suppressor genes, though methylation status has been shown to correlate with poor survival . Even if future preclinical studies will better clarify the mechanisms of action of these drugs on gene expression, preclinical findings will need to be validated in humans .
Despite these unresolved questions, epigenetic therapy is a promising approach for targeted anticancer therapies in pediatric STS. Available evidence suggests that targeting the methyltransferase EZH2 may be potentially able to restore physiological patterns of gene expression in pediatric STS. In the future, modulation of EZH2 activity may provide a new line of intervention that could be combined with epigenetic drugs acting on other molecular targets and/or conventional cytotoxic agents to treat these aggressive pediatric tumors.
The present work was supported by grants from Ministero della Sanità Italia (Ricerca Corrente), Associazione Italiana per la Ricerca sul Cancro (AIRC Project 10338) and Istituto Superiore di Sanità (ISS Project 70BF/8) to RR and by grants from Ministero della Salute, Italia (Ricerca Corrente) and AIRC (Special Project 5 × mille) to FL.
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