Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation

  1. Wesley L Cai
  2. Jocelyn Fang-Yi Chen
  3. Huacui Chen
  4. Emily Wingrove
  5. Sarah J Kurley
  6. Lok Hei Chan
  7. Meiling Zhang
  8. Anna Arnal-Estape
  9. Minghui Zhao
  10. Amer Balabaki
  11. Wenxue Li
  12. Xufen Yu
  13. Ethan D Krop
  14. Yali Dou
  15. Yansheng Liu
  16. Jian Jin
  17. Thomas F Westbrook
  18. Don X Nguyen  Is a corresponding author
  19. Qin Yan  Is a corresponding author
  1. University of Pittsburgh Medical Center, United States
  2. Yale University, United States
  3. Baylor College of Medicine, United States
  4. Icahn School of Medicine at Mount Sinai, United States
  5. University of Southern California, United States

Abstract

Metastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, combination of WDR5-targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.

Data availability

RNA-seq data have been deposited into the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus database under GSE196666. Reviewer token: qhqpeackxnebvqn.

The following data sets were generated

Article and author information

Author details

  1. Wesley L Cai

    Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  2. Jocelyn Fang-Yi Chen

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7281-8686
  3. Huacui Chen

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  4. Emily Wingrove

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  5. Sarah J Kurley

    Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  6. Lok Hei Chan

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  7. Meiling Zhang

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  8. Anna Arnal-Estape

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0490-7040
  9. Minghui Zhao

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  10. Amer Balabaki

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1509-886X
  11. Wenxue Li

    Department of Pharmacology, Yale University, West Haven, United States
    Competing interests
    No competing interests declared.
  12. Xufen Yu

    Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7794-7890
  13. Ethan D Krop

    Department of Pathology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  14. Yali Dou

    Department of Medicine, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
  15. Yansheng Liu

    Department of Pharmacology, Yale University, West Haven, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2626-3912
  16. Jian Jin

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    Jian Jin, . The Jin laboratory received research funds un-related to this study from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc. and Cullinan Oncology, Inc. J.J. is a cofounder, scientific advisory board member and equity shareholder in Cullgen, Inc. and a consultant for Cullgen, Inc., EpiCypher, Inc. and Accent Therapeutics, Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2387-3862
  17. Thomas F Westbrook

    Department of Molecular and Human Genetics, Baylor College of Medicine, Boston, United States
    Competing interests
    No competing interests declared.
  18. Don X Nguyen

    Department of Pathology, Yale University, New Haven, United States
    For correspondence
    don.nguyen@yale.edu
    Competing interests
    Don X Nguyen, has received research funding un-related to this study from AstraZeneca Inc..
  19. Qin Yan

    Department of Pathology, Yale University, New Haven, United States
    For correspondence
    qin.yan@yale.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4077-453X

Funding

National Science Foundation (Graduate Research FellowshipDGE-1122492)

  • Wesley L Cai

National Cancer Institute (F31CA243295)

  • Jocelyn Fang-Yi Chen

Congressionally Directed Medical Research Programs (W81XWH-15-1-0117 and W81XWH-21-1-0411)

  • Qin Yan

National Cancer Institute (R01CA237586)

  • Qin Yan

National Cancer Institute (R01CA166376)

  • Don X Nguyen

National Cancer Institute (P30CA016359)

  • Qin Yan

Yale Cancer Center (Class of '61 Cancer Research Award)

  • Qin Yan

Yale Cancer Center (Class of '61 Cancer Research Award)

  • Don X Nguyen

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 procedures have been approved by the Institutional Animal Care and Use Committee of Yale University under animal protocol 2021-11286.

Reviewing Editor

  1. Wilbert Zwart, Netherlands Cancer Institute, Netherlands

Publication history

  1. Received: February 25, 2022
  2. Accepted: August 24, 2022
  3. Accepted Manuscript published: August 31, 2022 (version 1)

Copyright

© 2022, Cai 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. Wesley L Cai
  2. Jocelyn Fang-Yi Chen
  3. Huacui Chen
  4. Emily Wingrove
  5. Sarah J Kurley
  6. Lok Hei Chan
  7. Meiling Zhang
  8. Anna Arnal-Estape
  9. Minghui Zhao
  10. Amer Balabaki
  11. Wenxue Li
  12. Xufen Yu
  13. Ethan D Krop
  14. Yali Dou
  15. Yansheng Liu
  16. Jian Jin
  17. Thomas F Westbrook
  18. Don X Nguyen
  19. Qin Yan
(2022)
Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation
eLife 11:e78163.
https://doi.org/10.7554/eLife.78163

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