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NSPc1 promotes cancer stem cell self-renewal by repressing the synthesis of all-trans retinoic acid via targeting RDH16 in malignant glioma

Oncogene volume 36, pages 4706–4718 (2017)Cite this article

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Abstract

Polycomb group (PcG) proteins play an important role in development and stem cell maintenance, and their dysregulation have been closely linked to oncogenesis and cancer stem cell phenotypes. Here, we found that nervous system polycomb 1 (NSPc1) was highly expressed in stem cell-like glioma cells (SLCs). Knockdown of NSPc1 in SLCs resulted in impaired neurosphere formation and self-renewal abilities, down-regulated expression of stemness markers such as NESTIN, CD133 and SOX2, and decreased capacity to propagate subcutaneous xenografts. In contrast, glioma cells overexpressing NSPc1 exhibited a stem cell-like phenotype, up-regulated expression of stemness markers NESTIN, CD133 and SOX2, and an enhanced capacity to propagate subcutaneous xenografts. Furthermore, we identified that NSPc1 epigenetically repressed the expression of retinol dehydrogenase 16 (RDH16) by directly binding to a region upstream (−1073 to −823) of the RDH16 promoter. Next, we confirmed that RDH16 is a stemness suppressor that partially rescues SLCs from the NSPc1-induced increase in neurosphere formation. Finally, we showed that ATRA partly reversed the NSPc1-induced stemness enhancement in SLCs, through mechanisms correlated with an ATRA-dependent decrease in the expression of NSPc1. Thus, our results demonstrate that NSPc1 promotes cancer stem cell self-renewal by repressing the synthesis of ATRA via targeting RDH16 and may provide novel targets for glioma treatment in the future.

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Acknowledgements

This work was supported by grants from The National Key Research and Development Plan (2016YFC0902502, 2016YFA0100702), 973 project No. 2013CB531304, National Sciences Foundation of China (31671316, 31301152, 31370789, 31670789), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-001, CIFMS, 2016-I2M-2-001, 2016-I2M-1-004). We thank Dr Zeper Abliz and Ruiping Zhang from the State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, for assistance with retinoid quantification.

Author contributions

PH and QX performed most of the experimental work, with assistance from FW, DL, YQ, YH, ZW, SL, NT, QW and LS. TJ provided fresh glioma samples and advice. PH and QX analysed the results, produced figures and wrote preliminary draft of the paper. BY, JY and BQ supervised and analysed results and edited the paper. WH and XP designed, supervised, and analysed experiments and wrote the final draft of the manuscript. All authors approved final version of the manuscript.

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  1. P-S Hu and Q-S Xia: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China

    P-S Hu, Q-S Xia, F Wu, D-k Li, Y-j Qi, Y Hu, Z-Z Wei, S-S Li, N-Y Tian, Q-F Wei, L-J Shen, B Yin, J-G Yuan, B-Q Qiang, W Han & X-Z Peng

  2. Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China

    T Jiang

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Hu, PS., Xia, QS., Wu, F. et al. NSPc1 promotes cancer stem cell self-renewal by repressing the synthesis of all-trans retinoic acid via targeting RDH16 in malignant glioma. Oncogene 36, 4706–4718 (2017). https://doi.org/10.1038/onc.2017.34

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