N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication

Abstract

N6-methyladenosine (m6A) 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 m6A as a crucial player in the occurrence and development of diseases, especially GI cancers. Among m6A regulators, YTHDF1 is the most abundant m6A reader that functionally connects m6A-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 m6A modified mRNA is an actionable target and a prognostic factor for GI cancers.

N6-methyladenosine modification of B7-H3 mRNA promotes the development and progression of colorectal cancer

“…Because the RNA-binding protein YTHDF1 was identified as a “reader” in m6A RNA modification and played a specific role in controlling the fate of methylated mRNA, 14 we investigated whether RNA m6A modification affects the interaction between YTHDF1 and B7-H3. We validated the mRNA and protein levels of B7-H3 in YTHDF1-overexpressing (DLD1 and HCT116) and YTHDF1-knockdown CRC cell lines (CACO2 and SW480).…”

“… 12 Additionally, in vitro and in vivo experiments supported the role of YTHDF1 in promoting cancer initiation, progression, and metastasis. 13 , 14 …”

YTHDF3-mediated m6A Modification Facilitates Osteosarcoma Progression through the FSP1-CoQ10-NAD(P)H Axis to Suppress Ferroptosis

“…N6-methyladenosine (m6A) stands as the most prevalent and ubiquitous mRNA modification, exercising pivotal roles and functionalities throughout a spectrum of biological processes. An accumulating body of evidence underscores the participation of m6A regulatory factors in various cancers, exerting significant roles in tumor cell proliferation and metastasis [9][10][11]. Reports have highlighted ALKBH5, a pivotal RNA demethylase, which, via an m6A-YTHDF2-dependent mechanism, orchestrates STAT3 activity, consequently impacting OS proliferation and oncogenicity [12].…”

YTHDF1’s grip on CRC vasculature: insights into LINC01106 and miR-449b-5p-VEGFA axis

“…In cancer, the expression level of YTHDF1 is closely correlated with tumor occurrence, progression, and prognosis [35,36]. For instance, YTHDF1 overexpression is associated with aggressive tumor behavior and poor prognosis in certain cancer types [37,38]. m6A modification plays an important role in tumor microenvironment regulation, particularly in tumor angiogenesis [39][40][41].…”