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

Wesley L. Cai, Jocelyn F. Chen, Huacui Chen, Emily Wingrove, Sarah J. Kurley, Lok Hei Chan, Meiling Zhang, Anna Arnal-Estapé, Minghui Zhao, Amer Balabaki, Wenxue Li, Xufen Yu, Ethan D. Krop, Yali Dou, Yansheng Liu, Jian Jin, Thomas F. Westbrook, Don X. Nguyen, Qin Yan

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Pages (from-to)1-76
Number of pages76
JournaleLife
Volume11
DOIs
StatePublished - 2022

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