Abstract
Ewing sarcoma is an aggressive cancer of bone and soft tissue in children. It is characterized by the chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI1. We recently reported that Ewing sarcoma depends on the autocrine signaling mediated by a cytokine, NELL2. NELL2 signaling stimulates the transcriptional output of EWS-FLI1 through the BAF chromatin remodeling complexes. While studying the impact of NELL2 silencing on Ewing sarcoma, we found that suppression of NELL2 signaling induces the expression of endogenous retroviruses (ERVs) and LINE-1 retrotransposons, an interferon response, and growth arrest. We determined that a histone methyltransferase, EZH2, is the critical downstream target of NELL2 signaling in suppressing ERVs, LINE-1, an interferon response, and growth arrest. We show that EZH2 inhibitors induce ERVs, LINE-1, and an interferon response in a variety of cancer types. These results uncover the role for NELL2–EZH2 signaling in suppressing endogenous virus-like agents and an antiviral response, and suggest the potential utility of EZH2 inhibitors in enhancing anti-tumor immunity.
Highlights
Ewing sarcoma is an aggressive bone and soft tissue cancer in children that is characterized by a chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI1 [1,2,3]
We discovered that NELL2 silencing by siRNA transfection or lentiviral shRNA expression results in the induction of interferon β1, interferon-stimulated genes (Mx1 and OAS1), and a cyclin-dependent kinase inhibitor p21 (CDKN1A) in Ewing sarcoma cells (Figure 1A–1F), which was suppressed by the addition of recombinant NELL2 protein to the culture medium (Figure 1G)
These results suggest that NELL2 signaling suppresses an interferon response in Ewing sarcoma
Summary
Ewing sarcoma is an aggressive bone and soft tissue cancer in children that is characterized by a chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI1 [1,2,3]. We identified EZH2 as a critical downstream target of NELL2 signaling in suppressing ERVs, LINE-1, and an interferon response. Suppression of NELL2 signaling induces an interferon response in Ewing sarcoma
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