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Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers

  1. Xuehui Hong
  2. He Huang
  3. Xingfeng Qiu
  4. Zhijie Ding
  5. Xing Feng
  6. Yuekun Zhu
  7. Huiqin Zhuo
  8. Jingjing Hou
  9. Jiabao Zhao
  10. Wangyu Cai
  11. Ruihua Sha
  12. Xinya Hong
  13. Yongxiang Li  Is a corresponding author
  14. Hongjiang Song  Is a corresponding author
  15. Zhiyong Zhang  Is a corresponding author
  1. Zunyi Medical College, China
  2. Xiangya School of Medicine, China
  3. Zhongshan Hospital of Xiamen University, China
  4. Rutgers University, United States
  5. The First Affiliated Hospital of Harbin Medical University, China
  6. Hongqi Hospital, Mudanjiang Medical University, China
  7. The First Affiliated Hospital of Anhui Medical University, China
  8. The Third Affiliated Hospital of Harbin Medical University, China
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Cite as: eLife 2018;7:e29511 doi: 10.7554/eLife.29511

Abstract

RIOK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RIOK1 is methylated at K411 by SETD7 methyltransferase and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RIOK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RIOK1. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1. Functional experiments demonstrate the RIOK1 methylation reduces the tumor growth and metastasis in mice model. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human colorectal cancer tissues. Together, this study highlights the importance of a RIOK1 methylation-phosphorylation switch in determining colorectal and gastric cancer development.

Article and author information

Author details

  1. Xuehui Hong

    Longju Medical Research Center, Zunyi Medical College, Zunyi, China
    Competing interests
    The authors declare that no competing interests exist.
  2. He Huang

    Department of Histology and Embryology, Xiangya School of Medicine, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Xingfeng Qiu

    Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Zhijie Ding

    Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Xing Feng

    Department of Radiation Oncology, Cancer Institute of New Jersey, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yuekun Zhu

    Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Huiqin Zhuo

    Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Jingjing Hou

    Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Jiabao Zhao

    Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Wangyu Cai

    Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Ruihua Sha

    Department of Digestive Disease, Hongqi Hospital, Mudanjiang Medical University, Mudangjiang, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Xinya Hong

    Department of Medical Imaging and Ultrasound, Zhongshan Hospital of Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Yongxiang Li

    Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Anhui, China
    For correspondence
    yongxiangli2001@outlook.com
    Competing interests
    The authors declare that no competing interests exist.
  14. Hongjiang Song

    Department of General Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, China
    For correspondence
    hongjiangsong2015@163.com
    Competing interests
    The authors declare that no competing interests exist.
  15. Zhiyong Zhang

    Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, New Brunswick, United States
    For correspondence
    zhiyongzhang@yahoo.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-8576-1607

Funding

National Natural Science Foundation of China (81602149)

  • Xuehui Hong

Natural Science Foundation of Fujian Province (2016J01619)

  • Xuehui Hong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed in accordance with NIH guidelines for the use of experimental animals. Male nonobese/severe combined immunodeficiency (NOD/SCID) mice between 4 and 6 weeks of age, obtained from the Experimental Animal Center of Shanghai Institute for Biological Sciences (SIBS). All animal work was conducted according to Institutional Animal Care Guidelines, and all animal experiments were approved by the ethical committee of the Harbin Medical University (Protocol Number: 20150619).

Human subjects: All human materials were obtained with informed consent and approved by the ethics committee of Hospital of Harbin Medical University (Protocol Number: 20150526).

Reviewing Editor

  1. Tony Hunter, Reviewing Editor, Salk Institute for Biological Studies, United States

Publication history

  1. Received: June 10, 2017
  2. Accepted: January 26, 2018
  3. Accepted Manuscript published: January 31, 2018 (version 1)
  4. Version of Record published: February 16, 2018 (version 2)

Copyright

© 2018, Hong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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