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Abstract Pediatric soft tissue sarcomas are rare tumors of childhood, frequently characterized by specific chromosome translocations. Despite improvements in treatment, their clinical management is often challenging due to the low responsiveness of metastatic forms and aggressive variants to conventional therapeutic approaches, which leads to poor overall survival. It is widely thought that soft tissue sarcomas derive from mesenchymal progenitor cells that, during embryonic life, have developed chromosomal aberrations with de-regulation of the main pathways governing tissue morphogenesis. The Notch signaling pathway is one of the most important molecular networks involved in differentiation processes. Emerging evidence highlights the role of Notch signaling de-regulation in the biology of these pediatric sarcomas. In this review, we present an outline of recently gathered evidence on the role of Notch signaling in soft tissue sarcomas, highlighting its importance in tumor cell biology. The potential challenges and opportunities of targeting Notch signaling in the treatment of pediatric soft tissue sarcomas are also discussed.

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.