Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
Cell Rep. 2021 Jul 6;36(1):109254. doi: 10.1016/j.celrep.2021.109254.
BAF chromatin remodeling complexes play important roles in chromatin regulation and cancer. Here, we report that Ewing sarcoma cells are dependent on the autocrine signaling mediated by NELL2, a secreted glycoprotein that has been characterized as an axon guidance molecule. NELL2 uses Robo3 as the receptor to transmit critical growth signaling. NELL2 signaling inhibits cdc42 and upregulates BAF complexes and EWS-FLI1 transcriptional output. We demonstrate that cdc42 is a negative regulator of BAF complexes, inducing actin polymerization and complex disassembly. Furthermore, we identify NELL2CD133EWS-FLI1 and NELL2CD133EWS-FLI1 populations in Ewing sarcoma, which display phenotypes consistent with high and low NELL2 signaling, respectively. We show that NELL2, CD133, and EWS-FLI1 positively regulate each other and upregulate BAF complexes and cell proliferation in Ewing sarcoma. These results reveal a signaling pathway regulating critical chromatin remodeling complexes and cancer cell proliferation.
BAF 染色质重塑复合物在染色质调控和癌症中发挥着重要作用。在这里，我们报告称，尤文肉瘤细胞依赖于 NELL2 介导的自分泌信号，NELL2 是一种已被确定为轴突导向分子的分泌糖蛋白。NELL2 使用 Robo3 作为受体传递关键的生长信号。NELL2 信号抑制 cdc42 并上调 BAF 复合物和 EWS-FLI1 的转录输出。我们证明 cdc42 是 BAF 复合物的负调节剂，诱导肌动蛋白聚合和复合物解体。此外，我们在尤文肉瘤中鉴定出了 NELL2CD133EWS-FLI1 和 NELL2CD133EWS-FLI1 群体，它们分别表现出与高和低 NELL2 信号一致的表型。我们表明，NELL2、CD133 和 EWS-FLI1 相互正调控，上调尤文肉瘤中的 BAF 复合物和细胞增殖。这些结果揭示了一条调节关键染色质重塑复合物和癌细胞增殖的信号通路。
