Jayabal Panneerselvam, Ma Xiuye, Shiio Yuzuru
Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
Genes Cancer. 2021 Dec 27;12:96-105. doi: 10.18632/genesandcancer.218. eCollection 2021.
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.
尤因肉瘤是儿童期一种侵袭性的骨和软组织癌症。其特征是EWS与Ets家族转录因子（最常见的是FLI1）之间发生染色体易位。我们最近报道，尤因肉瘤依赖于细胞因子NELL2介导的自分泌信号传导。NELL2信号通过BAF染色质重塑复合体刺激EWS-FLI1的转录输出。在研究NELL2沉默对尤因肉瘤的影响时，我们发现抑制NELL2信号会诱导内源性逆转录病毒（ERVs）和LINE-1逆转座子的表达、引发干扰素反应并导致生长停滞。我们确定组蛋白甲基转移酶EZH2是NELL2信号在抑制ERVs、LINE-1、干扰素反应和生长停滞方面的关键下游靶点。我们表明，EZH2抑制剂在多种癌症类型中均可诱导ERVs、LINE-1和干扰素反应。这些结果揭示了NELL2-EZH2信号在抑制内源性病毒样因子和抗病毒反应中的作用，并提示EZH2抑制剂在增强抗肿瘤免疫方面具有潜在效用。
