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

By Qin Yan, Jocelyn Fang-Yi Chen, Wesley Cai, Huacui Chen, Emily Wingrove, Sarah Kurley, Lok Hei Chan, Meiling Zhang, Anna Arnal-Estape, Minghui Zhao, Amer Balabaki, Wenxue Li, Xufen Yu, Yali Dou, Yansheng Liu, Jian Jin, Thomas F Westbrook, Don Nguyen

Posted 30 Mar 2022
bioRxiv DOI: 10.1101/2022.03.30.486357

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.

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