Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation
- University of Pittsburgh Medical Center, United States
- Yale University, United States
- Baylor College of Medicine, United States
- Icahn School of Medicine at Mount Sinai, United States
- 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.
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WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulationNCBI Gene Expression Omnibus, GSE196666.
Article and author information
Author details
Jocelyn Fang-Yi Chen
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.
Reviewing Editor
- Wilbert Zwart, Netherlands Cancer Institute, Netherlands
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.
Version history
- Received: February 25, 2022
- Preprint posted: March 30, 2022 (view preprint)
- Accepted: August 24, 2022
- Accepted Manuscript published: August 31, 2022 (version 1)
- Version of Record published: October 20, 2022 (version 2)
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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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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