YTHDF2 Regulates Cell Growth and Cycle by Facilitating KDM1A mRNA Stability

Breast cancer is the leading cause of cancer death in women. The physiological functions of N6methyladenosine methylation in cancer have been the focus of studies in recent years. Herein, four data sets (GSE70947, GSE45827, GSE42586, and The Cancer Genome Atlas Breast Cancer) were analyzed to confirm the differentially expressed N6-methyladenosine genes. YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2) was found to be highly expressed in breast cancer tissues and cells. In vitro, YTHDF2 affects cell proliferation, cell cycle, and invasive ability. Tumorigenesis in xenograft nude mice confirmed that YTHDF2 interference reduced the tumor formation ability of cancer cells. Pearson correlation analysis demonstrated a positive correlation between YTHDF2 and lysine-specific histone demethylase 1A (KDM1A) expression. An online tool, Sequence-based RNA Adenosine Methylation Site Predictor (SRAMP), predicted eight methylation sites in the KDM1A mRNA sequence. The expression of KDM1A was dramatically increased in breast cancer tissues and cells. Down-regulation of YTHDF2 reduced KDM1A expression and the methylation level of KDM1A mRNA. YTHDF2 interference promoted the degradation of KDM1A mRNA, which suggested an interaction between YTHDF2 and KDM1A. KDM1A interference altered cell proliferation, cell cycle, and invasive ability, whereas YTHDF2 overexpression rescued KDM1A interference-induced cell phenotypic changes. In conclusion, YTHDF2 promotes breast cancer cell growth and cell cycle progression by facilitating KDM1A mRNA stability. This study provides new therapeutic targets for breast cancer treatment in the future. (Am J Pathol 2023, 193: 442-455; https://doi.org/10.1016/j.ajpath.2022.12.010)