Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications
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MINIREVIEW
Open Access
Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications Roberta Ciarapica1*, Lucio Miele2, Antonio Giordano3,4, Franco Locatelli1,5 and Rossella Rota1*
Abstract 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. Keywords: EZH2, soft tissue sarcomas, epigenetics, methylation, methyltransferases
* Correspondence: [email protected]; [email protected] 1 Department of Oncohematology, IRCCS, Ospedale Pediatrico Bambino Gesù, Roma, Italy Full list of author information is available at the end of the article
Introduction Soft tissue sarcomas: a clinical challenge
Soft tissue sarcomas (STSs) are a group of heterogeneous malignant neoplasms thought to arise from molecular lesions occurring during the differentiation of mesenchymal stem cells (MSCs) [1]. STSs account for less than 1% of all adult tumors and for about 15% of all pediatric ones, with an estimated 10,520 new cases in the US in 2010 [2,3]. A series of chromosomal translocations have been identified as hallmarks of most STSs, such as t(X;18)(p11.2;q11.2) in synovial sarcoma, t (11;22)(q24;q12) in Ewing’s sarcoma, t(2;13)(q35;q14) and t(1;13)(p36;q14) in alveolar rhabdomyosarcoma (RMS). These chromosomal rearrangements result in oncogenic fusion proteins that play direct roles in altering gene expression pattern in STS, promoting tumor aggressiveness. Because of their infiltrating behavior, only 50% of STSs are suitable for radical surgical resection. Moreover, a fraction of STSs are resistant to chemotherapeutic agents, especially the metastatic forms [4]. Doxorubicin, the drug used in standard single-agent chemotherapy protocols for the treatment of metastatic STS, results in only 20% to 25% response rates. Even the combination of doxorubicin with other agents, such as ifosfamide, has not dramatically improved the ov
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