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β-Trcp ubiquitin ligase and RSK2 kinase-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer

Cell Death & Differentiation (2018) | Download Citation

Abstract

Aberrant expression of FOXN2, a member of the Forkhead box transcription factors, has been found in several types of cancer. However, the underlying mechanisms of FOXN2 deregulation in tumorigenesis remain largely unknown. Here, we find that FOXN2 binds to and is ubiquitinated by β-Trcp ubiquitin ligase and RSK2 kinase for degradation. Furthermore, we demonstrate that the Ser365 and Ser369 sites in a conserved DSGYAS motif are critical for the degradation of FOXN2 by β-Trcp and RSK2. Moreover, gain-of-function and loss-of-function studies show that FOXN2 impairs cell proliferation in vitro and in vivo and enhances the radiosensitivity of lung cancer. Importantly, β-Trcp-mediated and RSK2-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer cells. Collectively, our study reveals a novel post-translational modification of FOXN2 and suggests that FOXN2 may be a potential therapeutic and radiosensitization target for lung cancer.

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Acknowledgements

This work was supported by National Key R&D Program of China (2016YFC0106700 to GW and SZ), National Key R&D Program of China (2016YFC1303800 to LL), the National Natural Science Foundation of China (81672289 to SX), a grant from the Wuhan Science and Technology Bureau (2015060101010041 to SX), and the National Natural Science Foundation of China (81372435 to KY).

Author contributions’

SX designed and conceived the study. JM, YL, and SZ performed experiments and analyzed the data. YL, JH, ZY, JR, KH, LL, KY, and GW provided advice and technical assistance, SX wrote the manuscript. All authors have contributed to and approved the final manuscript.

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Author notes

  1. V D'Angiolella

  2. Jia Ma, Yanwei Lu, and Sheng Zhang contributed equally to this work.

Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    • Jia Ma
    • , Yanwei Lu
    • , Sheng Zhang
    • , Yan Li
    • , Jing Huang
    • , Zhongyuan Yin
    • , Jinghua Ren
    • , Li Liu
    • , Kunyu Yang
    • , Gang Wu
    •  & Shuangbing Xu
  2. Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    • Kai Huang

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The authors declare that they have no conflict of interest.

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Correspondence to Shuangbing Xu.

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DOI

https://doi.org/10.1038/s41418-017-0055-6

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