The m⁶A Reader YTHDF1 Facilitates the Tumorigenesis and Metastasis of Gastric Cancer via USP14 Translation in an m⁶A-Dependent Manner

Objectives: N⁶-methyladenosine (m⁶A) RNA methylation is implicated in the progression of multiple cancers via influencing mRNA modification. YTHDF1 can act as an oncogene in gastric cancer (GC), while the biological mechanisms via which YTHDF1 regulates gastric tumorigenesis through m⁶A modification remain largely unknown.

Methods: GEO and TCGA cohorts were analyzed for differentially expressed m⁶A modification components in GC clinical specimens and their association with clinical prognosis. Transwell and flow cytometry assays as well as subcutaneous xenograft and lung metastasis models were used to evaluate the phenotype of YTHDF1 in GC. Intersection of RNA/MeRIP-seq, luciferase assay, RIP-PCR, RNA pull-down and MeRIP-PCR was used to identify YTHDF1- modified USP14 and its m⁶A levels in GC cells.

Results: High-expressed YTHDF1 was found in GC tissues and was related to poor prognosis, acting as an independent prognostic factor of poor survival in GC patients. YTHDF1 deficiency inhibited cell proliferation and invasion (in vitro), and gastric tumorigenesis and lung metastasis (in vivo) and also induced cell apoptosis. Intersection assays revealed that YTHDF1 promoted USP14 protein translation in an m⁶A-dependent manner. USP14 upregulation was positively correlated with YTHDF1 expression and indicated a poor prognosis in GC.

Conclusion: Our data suggested that m⁶A reader YTHDF1 facilitated tumorigenesis and metastasis of GC by promoting USP14 protein translation in an m⁶A-dependent manner and might provide a potential target for GC treatment.