Nuclear receptor NR1D2 is originally characterized as the repressor of genes involved in circadian rhythm. Recently, it is documented that NR1D2 is overexpressed in various cancers. However, the pathways and biological functions that NR1D2 involved in cancers remain poorly understood. Here, we reported that NR1D2 was abundant in human glioblastoma (GBM) tissue and cell lines but not primary human astrocytes. Silencing of NR1D2 changed the morphology of GBM cells, inhibited cell proliferation and motility, whereas had no effects on apoptosis. Importantly, based on RNA-seq and ChIP assay, we identified receptor tyrosine kinase AXL as a new transcriptional target of NR1D2 in GBM cells. AXL mediated partially the regulatory effects of NR1D2 on PI3K/AKT axis and promoted proliferation, migration, and invasion of GBM cells. Besides, NR1D2 knockdown remarkably impaired the maturation of focal adhesion and assembly of F-actin, along with downregulated p-FAK, and proteins involved in actin nucleation and polymerization (p-Rac1/Cdc42, WAVE and PFN2). Moreover, NR1D2 had more targets other than AXL to regulate epithelial-to-mesenchymal transition and cell motility in GBM cells. Altogether, our findings uncover a GBM-promoting role of NR1D2 and provide the rationale for targeting NR1D2 as a potential therapeutic approach.

中文翻译：

---

昼夜节律调节器NR1D2调节胶质母细胞瘤细胞的增殖和运动。

核受体NR1D2最初被表征为涉及昼夜节律的基因的阻遏物。最近，有文献证明NR1D2在各种癌症中过表达。但是，NR1D2参与癌症的途径和生物学功能仍然知之甚少。在这里，我们报告说，NR1D2在人胶质母细胞瘤（GBM）组织和细胞系中含量很高，但在原代人星形胶质细胞中却没有。NR1D2的沉默改变了GBM细胞的形态，抑制了细胞的增殖和运动，而对细胞凋亡没有影响。重要的是，基于RNA-seq和ChIP分析，我们确定了受体酪氨酸激酶AXL是GBM细胞中NR1D2的新转录靶标。AXL部分介导NR1D2对PI3K / AKT轴的调节作用，并促进GBM细胞的增殖，迁移和侵袭。除了，NR1D2敲低显着损害F-肌动蛋白的粘着斑和组装的成熟，以及下调的p-FAK和参与肌动蛋白成核和聚合反应的蛋白（p-Rac1 / Cdc42，WAVE和PFN2）。此外，NR1D2除AXL以外还具有更多的靶标来调节GBM细胞的上皮-间充质转化和细胞运动。总之，我们的发现揭示了NR1D2在GBM中的促进作用，并提供了将NR1D2靶向作为潜在治疗方法的理由。