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FHL3 links cell growth and self-renewal by modulating SOX4 in glioma

Cell Death & Differentiation (2018) | Download Citation

Abstract

Differentiation status significantly affects the properties of malignant glioma cells, with non-stem cells inducing tumor enlargement and stem-like cells driving tumor initiation and treatment resistance. It is not completely understood how the same protein can have a distinct role in these cell populations. Here, we report that four and a half LIM domain protein 3 (FHL3) has an inhibitory effect on proliferation in non-stem glioma cells and a non-proliferative effect in glioma stem cells (GSCs). In GSCs, we show that FHL3 interacts with the Smad2/3 protein complex at the SOX4 promoter region, inhibits SOX4 transcriptional activity by recruiting PPM1A phosphatase to Smad2/3, and then suppresses GSC tumor sphere formation and self-renewal in vitro and in vivo via downregulation of SOX2 expression. Altogether, these findings highlight the role of FHL3 as a stemness-suppressor in regulation of the Smad2/3–SOX4–SOX2 axis in glioma.

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Acknowledgements

This study was supported by the following grants—The National Key Research and Development Program of China (2016YFC0902502, 2016YFA0100702), and National Sciences Foundation of China (31671316, 31670789), CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-1-001, 2016-I2M-2-001, 2016-I2M-1-004, 2017-I2M-2-004, 2017-I2M-3-010, 2017-I2M-1-004), Peking Union Medical College Youth Fund, and the Fundamental Research Funds for the Central Universities (3332013052, 3332014006).

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Author notes

  1. These authors contributed equally: Wei Han, Peishan Hu.

Affiliations

  1. State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China

    • Wei Han
    • , Peishan Hu
    • , Fan Wu
    • , Shanshan Wang
    • , Yan Hu
    • , Shanshan Li
    • , Boqin Qiang
    •  & Xiaozhong Peng
  2. Institute of Medical Biology, Chinese Academy of Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, 650118, Kunming, China

    • Xiaozhong Peng
  3. Department of Neurosurgery, Beijing Tiantan Hospital, 100050, Beijing, China

    • Fan Wu
    •  & Tao Jiang

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The authors declare that they have no conflict of interest.

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Correspondence to Boqin Qiang or Xiaozhong Peng.

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DOI

https://doi.org/10.1038/s41418-018-0152-1