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.
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.
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
Further reading
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TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.
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