ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer

  1. Wentong Fang
  2. Chengheng Liao  Is a corresponding author
  3. Rachel Shi
  4. Jeremy M Simon
  5. Travis S Ptacek
  6. Giada Zurlo
  7. Youqiong Ye
  8. Leng Han
  9. Cheng Fan
  10. Lei Bao
  11. Christopher Llynard Ortiz
  12. Hong-Rui Lin
  13. Ujjawal Manocha
  14. Weibo Luo
  15. William Y Kim
  16. Lee-Wei Yang
  17. Qing Zhang  Is a corresponding author
  1. The First Affiliated Hospital of Nanjing Medical University, China
  2. University of Texas Southwestern Medical Center, United States
  3. University of North Carolina School of Medicine, United States
  4. The University of Alabama at Birmingham, United States
  5. Shanghai Jiao Tong University School of Medicine, China
  6. The University of Texas Health Science Center at Houston McGovern Medical School, United States
  7. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan
  8. The University of Texas Southwestern Medical Center, United States
  9. National Tsing Hua University, Taiwan

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers and Homeoboxes 2 (ZHX2) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia inducible factor (HIF) family members and positively regulated HIF1a activity in TNBC. Integrated ChIP-Seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1a on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Among the identified ZHX2 and HIF1a co-regulated genes, overexpression of AP2B1, COX20, KDM3A, or PTGES3L could partially rescue TNBC cell growth defect by ZHX2 depletion, suggested that these downstream targets contribute to the oncogenic role of ZHX2 in an accumulative fashion. Furthermore, multiple residues (R491, R581 and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling ZHX2 transcriptional activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1a signaling, therefore serving as a potential therapeutic target for TNBC.

Data availability

•Sequencing data have been deposited in GEO under accession codes GSE175487

The following data sets were generated

Article and author information

Author details

  1. Wentong Fang

    The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0047-1198
  2. Chengheng Liao

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    chengheng.liao@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
  3. Rachel Shi

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeremy M Simon

    Neuroscience Center; Carolina Institute for Developmental Disabilities; Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3906-1663
  5. Travis S Ptacek

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Giada Zurlo

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Youqiong Ye

    Shanghai Institute of Immunology, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Leng Han

    The University of Texas Health Science Center at Houston McGovern Medical School, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Cheng Fan

    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Lei Bao

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Christopher Llynard Ortiz

    Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3114-7369
  12. Hong-Rui Lin

    Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
  13. Ujjawal Manocha

    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Weibo Luo

    Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. William Y Kim

    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Lee-Wei Yang

    Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3971-6386
  17. Qing Zhang

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    qing.zhang@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6595-8995

Funding

National Cancer Institute (R01CA211732)

  • Qing Zhang

National Cancer Institute (R01CA256833)

  • Qing Zhang

Cancer Prevention and Research Institute of Texas (RR190058)

  • Qing Zhang

American Cancer Society (RSG-18-059-01-TBE)

  • Qing Zhang

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

Reviewing Editor

  1. Caigang Liu, Shengjing Hospital of China Medical University, China

Ethics

Animal experimentation: All animal experiments were in compliance with National Institutes of Health guidelines and were approved by the University of Texas, Southwestern Medical Center Institutional Animal Care and Use Committee.

Version history

  1. Received: May 16, 2021
  2. Preprint posted: May 28, 2021 (view preprint)
  3. Accepted: November 14, 2021
  4. Accepted Manuscript published: November 15, 2021 (version 1)
  5. Accepted Manuscript updated: November 18, 2021 (version 2)
  6. Version of Record published: December 15, 2021 (version 3)

Copyright

© 2021, Fang 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. Wentong Fang
  2. Chengheng Liao
  3. Rachel Shi
  4. Jeremy M Simon
  5. Travis S Ptacek
  6. Giada Zurlo
  7. Youqiong Ye
  8. Leng Han
  9. Cheng Fan
  10. Lei Bao
  11. Christopher Llynard Ortiz
  12. Hong-Rui Lin
  13. Ujjawal Manocha
  14. Weibo Luo
  15. William Y Kim
  16. Lee-Wei Yang
  17. Qing Zhang
(2021)
ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer
eLife 10:e70412.
https://doi.org/10.7554/eLife.70412

Share this article

https://doi.org/10.7554/eLife.70412

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