Ewing's sarcoma (ES) is a malignant tumor that can be defined by the characteristic chromosomic translocation t(11;22)(q24;q12), which then leads to the formation of the fusion protein EWS-FLI1, responsible for malignant transformation. The expression of many genes can be modified by EWS-FLI1 in ES, including EZH2 (Enhancer of Zeste, Drosophila, Homolog 2). This methyltransferase is a member of the Polycomb group genes, which are capable of inducing epigenetic modifications that silence or induce target gene expression. EZH2 is part of the Polycomb Repressive Complex 2 (PRC2), which inhibits DNA transcription by adding a trimethyl group to histone H3. This provides a mechanism by which EZH2 can participate in generating conditions that help maintain the cell at a stem-like state.
While expression of EWS-FLI1 in primary cells has not been successful, primarily due to an oncogenic stress response, mesenchymal stem cells (MSCs) were able to survive and successfully express EWS-FLI1. Therefore, it is likely that plasticity is important for cells to sustain overexpression of EWS-FLI1. Thus, inducing EZH2 expression could possibly increase cell permissiveness to EWS-FLI1 expression.
This work shows that, following transduction of fibroblasts with EZH2, primary cells become more permissive and are capable of expressing EWS- FLI1. Thus, EZH2 provides a permissive environment for oncogenic transformation.