YTHDF3 drives tumor growth and metastasis by recruiting eIF4B to promote Notch2 translation in breast cancer

Abstract

YTH domain family protein 3 (YTHDF3), an m⁶A RNA reader, is implicated in various cancers, but its role in breast cancer progression and metastasis remains unclear. In this study, we explore the oncogenic potential of YTHDF3 in breast cancer, focusing on its impact on epithelial-mesenchymal transition (EMT) and metastasis. We found that YTHDF3 is significantly upregulated in breast cancer tissues and associated with poor relapse-free survival (RFS). Functional studies demonstrated that YTHDF3 promotes EMT in breast cancer cell lines by enhancing cell migration, invasion, and metastasis in vivo. Mechanistically, we show that YTHDF3 regulates Notch2, a key driver of EMT, through an m⁶A-dependent mechanism. YTHDF3 binds to m⁶A-modified Notch2 mRNA and recruits eIF4B to facilitate its translation, leading to increased Notch2 translation and subsequent inducing EMT. Our findings highlight the importance of the YTHDF3-Notch2 axis in driving EMT and metastasis in breast cancer. Furthermore, targeting YTHDF3 with lipid nanoparticles (LNPs) encapsulating siRNA and indocyanine green (ICG) significantly suppressed tumor growth and lung metastasis while enabling real-time therapeutic monitoring via ICG fluorescence imaging. These findings establish YTHDF3 as a critical driver of EMT and metastasis through m⁶A-dependent Notch2 translation, highlighting its potential as a therapeutic target in breast cancer.