Genes & Cancer: EZH2 suppresses endogenous retroviruses and an interferon response in cancers (Shiio Lab)
Ewing sarcoma is an aggressive cancer of the 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 interferon response in a variety of cancer types. These results uncover the role of NELL2–EZH2 signaling in suppressing endogenous virus-like agents and antiviral response and suggest the potential utility of EZH2 inhibitors in enhancing anti-tumor immunity.
Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to the understanding of its causes, and accelerate the translation of knowledge into novel therapies. Greehey CCRI strives to have a national and global impact on childhood cancer through the discovery, development, and dissemination of new scientific knowledge. Our mission consists of three key areas — research, clinical, and education.