N(6)-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication

SIMPLE SUMMARY: N(6)-methyladenosine (m(6)A) is the most abundant internal modification in eukaryotic mRNA and plays a crucial role in the occurrence and development of diseases. YTHDF1 is the most powerful and abundant m(6)A-encoded RNA reader. In this review, we summarize the evidence of the involvement of YTHDF1 in gastrointestinal cancers, its molecular mechanisms of action, and therapeutic implications. ABSTRACT: N(6)-methyladenosine (m(6)A) is the most abundant internal modification in eukaryotic cell mRNA, and this modification plays a key role in regulating mRNA translation, splicing, and stability. Emerging evidence implicates aberrant m(6)A as a crucial player in the occurrence and development of diseases, especially GI cancers. Among m(6)A regulators, YTHDF1 is the most abundant m(6)A reader that functionally connects m(6)A-modified mRNA to its eventual fate, mostly notably protein translation. Here, we summarized the function, molecular mechanisms, and clinical implications of YTHDF1 in GI cancers. YTHDF1 is largely upregulated in multiple GI cancer and its high expression predicts poor patient survival. In vitro and in vivo experimental evidence largely supports the role of YTDHF1 in promoting cancer initiation, progression, and metastasis, which suggests the oncogenic function of YTHDF1 in GI cancers. Besides, YTHDF1 overexpression is associated with changes in the tumor microenvironment that are favorable to tumorigenesis. Mechanistically, YTHDF1 regulates the expression of target genes by promoting translation, thereby participating in cancer-related signaling pathways. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy. In summary, YTHDF1-mediated regulation of m(6)A modified mRNA is an actionable target and a prognostic factor for GI cancers.