YTHDF3 facilitates triple-negative breast cancer progression and metastasis by stabilizing ZEB1 mRNA in an m6A-dependent manner

作者：Yuxiang Lin, Xuan Jin, Qian Nie, Minyan Chen, Wenhui Guo, Lili Chen, Yan Li, Xiaobin Chen, Wenzhe Zhang, Hanxi Chen, Meichen Jiang, Xiao Han, Jie Zhang, Fangmeng Fu, Chuan Wang · 发表于：Annals of Translational Medicine · 年份：2022 · DOI：10.21037/atm-21-6857 · 被引用次数：57 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Cancer-related molecular mechanisms research

Background: The YTH domain family protein 3 (YTHDF3) is an important N6-methyladenosine (m6A) reader which is involved in multiple cancers. However, the biological role and mechanisms of action for YTHDF3 in triple-negative breast cancer (TNBC) remains to be elucidated. Methods: The expression of YTHDF3 in TNBC tissues was evaluated using The Cancer Genome Atlas (TCGA) database, BC-GenExMiner, and immunohistochemistry (IHC) staining. Cell migration, invasion, and epithelial-mesenchymal transition (EMT) were validated by wound healing assays, transwell assays, and Western blot (WB) analyses. The association between YTHDF3 and zinc finger E-box-binding homeobox 1 (ZEB1) was confirmed by Pearson correlation analysis. RNA-binding protein immunoprecipitation (RIP) assays and mRNA actinomycin stability analyses were applied to confirm whether YTHDF3 could interact with ZEB1in an m6A-dependent manner. Results: The expression of YTHDF3 was correlated with poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Functional experiments indicated that YTHDF3 positively regulated cell migration, invasion, and EMT in TNBC cells. Moreover, ZEB1 was identified as a key downstream target for YTHDF3 and YTHDF3 could enhance ZEB1 mRNA stability in an m6A-dependent manner. Inhibition of YTHDF3 reduced migration, invasion, and EMT, all of which were reversed by rescue experiments overexpressing ZEB1. Conclusions: The findings herein confirmed that the YTHDF3/ZEB1 axis plays...