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Circadian regulator NR1D2 regulates glioblastoma cell proliferation and motility

Oncogene volume 37, pages 4838–4853 (2018)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by grants from Natural Science Foundation of Guangdong Province (grant no. 2014A030313779), Shenzhen basic research program (grant no. JCYJ20160527100529884 and JCYJ20170818085657917). We thank Dr. Hui Zhang for the kind gift of U-373 MG cell line.

Author contributions

F.L. and M.Y. perceived the conception, analyzed the findings, and wrote the manuscript; M.Y. executed most of the experiments. W.L., Q.W. assisted in execution of some experiments, and Y.W. provided tumor specimens. All authors reviewed the results and approved the final version of the manuscript.

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  1. State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China

    Min Yu, Wenjing Li, Qianqian Wang & Fei Lu

  2. Department of Cardiology, Qingdao Municipal Hospital, Qingdao University, Qingdao, 266011, China

    Yan Wang

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Correspondence to Fei Lu.

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Yu, M., Li, W., Wang, Q. et al. Circadian regulator NR1D2 regulates glioblastoma cell proliferation and motility. Oncogene 37, 4838–4853 (2018). https://doi.org/10.1038/s41388-018-0319-8

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