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YTH Domain Family 2 (YTHDF2) Regulates Cell Growth and Cycle by Facilitating KDM1A mRNA Stability

  • Xin Li
    Affiliations
    ∗Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province, Changsha, China
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  • KeJing Zhang
    Affiliations
    ∗Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province, Changsha, China
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  • Yu Hu
    Affiliations
    ∗Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province, Changsha, China
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  • Na Luo
    Correspondence
    Address correspondence to Na Luo, Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Rd., Changsha, Hunan, China.
    Affiliations
    ∗Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province, Changsha, China
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Published:January 18, 2023DOI:https://doi.org/10.1016/j.ajpath.2022.12.010
      Breast cancer is the leading cause of cancer death in women. More than one million women worldwide are diagnosed with breast cancer each year, and the incidence rates are increasing. The physiological functions of N6-methyladenosine methylation in cancer have been appreciated 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. YTHDF2 was found to be highly expressed in breast cancer tissues and cells. In vitro, YTHDF2 affects cell proliferation, the 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 KDM1A. An online tool (SRAMP) predicted that there are 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.
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