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

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, a 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.

Automated summary

Metastatic breast cancer is a leading cause of cancer-related deaths in women, with limited effective therapies available. Research has shown that reversible epigenetic mechanisms play a crucial role in tumor progression and metastasis. A recent study identified WDR5 as an actionable epigenetic regulator that is necessary for metastatic progression in triple-negative breast cancer models. Knockdown of WDR5 in breast cancer cells impairs their tumorigenic and metastatic capabilities, likely through increasing ribosomal gene expression and translation efficiency. Inhibition or degradation of WDR5 hampers cellular translation rate and clonogenic ability. Combining WDR5 targeting with mTOR inhibitors leads to potent suppression of translation and proliferation in breast cancer cells. These findings provide new therapeutic strategies for treating metastatic breast cancer.