Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation
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, 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 31, 2022
- Source ID
- 10.7554/elife.78163
Entities
People
- Amer Balabaki
- Anna Arnal-Estapé
- Don X. Nguyen
- Emily Wingrove
- Ethan D Krop
- Huacui Chen
- Jian Jin
- Jocelyn Fang-Yi Chen
- Lok Hei Chan
- Meiling Zhang
- Minghui Zhao
- Qin Yan
- Sarah J Kurley
- Thomas F. Westbrook
- Wenxue Li
- Wesley Cai
- Xufen Yu
- Yali Dou
- Yansheng Liu
Organizations
- Baylor College of Medicine
- Congressionally Directed Medical Research Programs
- Icahn School of Medicine at Mount Sinai
- National Cancer Institute
- National Institutes of Health
- National Science Foundation
- Rice University
- University of Michigan
- University of Pittsburgh Medical Center
- University of Southern California
- Yale Cancer Center
- Yale School of Medicine
- Yale University