Epigenetic and epigenomic mechanisms shape sarcoma and other mesenchymal tumor pathogenesis

Abstract

Sarcomas comprise a large number of rare, histogenetically heterogeneous, mesenchymal tumors. Cancers such as Ewing’s sarcoma, liposarcoma, rhabdomyosarcoma and synovial sarcoma can be generated by the transduction of mesenchymal stem cell progenitors with sarcoma-pathognomonic oncogenic fusions, a neoplastic transformation process accompanied by profound locus-specific and pangenomic epigenetic alterations. The epigenetic activities of histone-modifying and chromatin-remodeling enzymes such as SUV39H1/KMT1A, EZH2/KMT6A and BMI1 are central to epigenetic-regulated transformation, a property we coin oncoepigenic. Sarcoma-specific oncoepigenic aberrations modulate critical signaling pathways that control cell growth and differentiation including several miRNAs, Wnt, PI3K/AKT, Sav-RASSF1-Hpo and regulators of the G1 and G2/M checkpoints of the cell cycle. Herein an overview of the current knowledge of this rapidly evolving field that will undoubtedly uncover additional oncoepigenic mechanisms and yield druggable targets in the near future is discussed.