EZH2 suppresses endogenous retroviruses and an interferon response in cancers
Panneerselvam Jayabal1, Xiuye Ma1, Yuzuru Shiio1,2,3
1 Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
2 Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
3 Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Correspondence:
Yuzuru Shiio, email:[email protected]
Keywords: endogenous retroviruses; Ewing sarcoma; EZH2; interferon response; NELL2
Received: June 07, 2021 Accepted: December 23, 2021 Published: December 27, 2021
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.
