Abstract

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin–proteasome pathway. SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE193133.All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-6 and Figure S1-5.

The following data sets were generated

Article and author information

Author details

  1. Qiangqiang Liu

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Qian Luo

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Jianyu Feng

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yanping Zhao

    School of Statistics and Data Science, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Biao Ma

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Hongcheng Cheng

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Tian Zhao

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Hong Lei

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Chenglong Mu

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Linbo Chen

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Yuanyuan Meng

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Jiaojiao Zhang

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Yijia Long

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Jingyi Su

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Guo Chen

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Yanjun Li

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  17. Gang Hu

    School of Statistics and Data Science, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Xudong Liao

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  19. Quan Chen

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  20. Yushan Zhu

    College of Life Sciences, Nankai University, Tianjin, China
    For correspondence
    zhuys@nankai.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5648-0416

Funding

National Key Research and Development Program of China (2019YFA0508603)

  • Yushan Zhu

National Natural Science Foundation of China (32030026)

  • Yushan Zhu

National Natural Science Foundation of China (31271529)

  • Quan Chen

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

Reviewing Editor

  1. Qing Zhang, University of Texas Southwestern Medical Center, United States

Ethics

Animal experimentation: Mice were maintained in the animal core facility of College of Life Sciences, Nankai University, Tianjin, China. All experiments involving animals were reviewed and approved by the Animal Care and Use Committee of Nankai University and were performed in accordance with the university guidelines (NO. 2022-SYDWLL-000353).

Version history

  1. Preprint posted: January 11, 2022 (view preprint)
  2. Received: June 20, 2022
  3. Accepted: July 19, 2022
  4. Accepted Manuscript published: August 1, 2022 (version 1)
  5. Version of Record published: August 15, 2022 (version 2)

Copyright

© 2022, Liu 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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  1. Qiangqiang Liu
  2. Qian Luo
  3. Jianyu Feng
  4. Yanping Zhao
  5. Biao Ma
  6. Hongcheng Cheng
  7. Tian Zhao
  8. Hong Lei
  9. Chenglong Mu
  10. Linbo Chen
  11. Yuanyuan Meng
  12. Jiaojiao Zhang
  13. Yijia Long
  14. Jingyi Su
  15. Guo Chen
  16. Yanjun Li
  17. Gang Hu
  18. Xudong Liao
  19. Quan Chen
  20. Yushan Zhu
(2022)
Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression
eLife 11:e81247.
https://doi.org/10.7554/eLife.81247

Share this article

https://doi.org/10.7554/eLife.81247

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