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

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 "This ORCID iD identifies the author of this article:" 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, Salk Institute for Biological Studies, United States

Version 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.

Metrics

  • 2,182
    Page views
  • 403
    Downloads
  • 44
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
  14. Hongjiang Song
  15. Zhiyong Zhang
(2018)
Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers
eLife 7:e29511.
https://doi.org/10.7554/eLife.29511

Further reading

    1. Cancer Biology
    Elena Farmaki, Aritro Nath ... Andrea H Bild
    Research Article

    The mTOR inhibitor, everolimus, is an important clinical management component of metastatic ER+ breast cancer (BC). However, most patients develop resistance and progress on therapy, highlighting the need to discover strategies that increase mTOR inhibitor effectiveness. We developed ER+ BC cell lines, sensitive or resistant to everolimus, and discovered that combination treatment of ONC201/TIC10 with everolimus inhibited cell growth in 2D/3D in vitro studies. We confirmed increased therapeutic response in primary patient cells progressing on everolimus, supporting clinical relevance. We show that ONC201/TIC10 mechanism in metastatic ER+ BC cells involves oxidative phosphorylation inhibition and stress response activation. Transcriptomic analysis in everolimus resistant breast patient tumors and mitochondrial functional assays in resistant cell lines demonstrated increased mitochondrial respiration dependency, contributing to ONC201/TIC10 sensitivity. We propose that ONC201/TIC10 and modulation of mitochondrial function may provide an effective add-on therapy strategy for patients with metastatic ER+ BCs resistant to mTOR inhibitors.

    1. Cancer Biology
    2. Computational and Systems Biology
    Megan E Kelley, Adi Y Berman ... Gregory P Way
    Research Article

    Drug resistance is a challenge in anticancer therapy. In many cases, cancers can be resistant to the drug prior to exposure, i.e., possess intrinsic drug resistance. However, we lack target-independent methods to anticipate resistance in cancer cell lines or characterize intrinsic drug resistance without a priori knowledge of its cause. We hypothesized that cell morphology could provide an unbiased readout of drug resistance. To test this hypothesis, we used HCT116 cells, a mismatch repair-deficient cancer cell line, to isolate clones that were resistant or sensitive to bortezomib, a well-characterized proteasome inhibitor and anticancer drug to which many cancer cells possess intrinsic resistance. We then expanded these clones and measured high-dimensional single-cell morphology profiles using Cell Painting, a high-content microscopy assay. Our imaging- and computation-based profiling pipeline identified morphological features that differed between resistant and sensitive cells. We used these features to generate a morphological signature of bortezomib resistance. We then employed this morphological signature to analyze a set of HCT116 clones (five resistant and five sensitive) that had not been included in the signature training dataset, and correctly predicted sensitivity to bortezomib in seven cases, in the absence of drug treatment. This signature predicted bortezomib resistance better than resistance to other drugs targeting the ubiquitin-proteasome system. Our results establish a proof-of-concept framework for the unbiased analysis of drug resistance using high-content microscopy of cancer cells, in the absence of drug treatment.