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

Xiao-Yu Chen,You-Cai Yi,Rui Liang,Ming Chen,Hui-Ning Fan,Jin-Shui Zhu,Jing Zhang

doi:10.3389/fcell.2021.647702

Abstract

ObjectivesN6-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.MethodsGEO 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.ResultsHigh-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.ConclusionOur 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.

Highlights

According to the global cancer statistics, gastric cancer (GC) is regarded as one of the most invasive cancers and is the third leading factor of tumor-associated deaths (Bray et al, 2018)
We measured the expression of these m6A-related members in 418 patients with GC from The Cancer Genome Atlas (TCGA) (n = 292) and GSE29272 (n = 126) databases
YTHDF1 expression was significantly increased both in gastric cardia adenocarcinoma (GCA) and gastric non-cardia adenocarcinoma (GNCA) according to the GSE29272 dataset compared with their pair-matched normal tissues (Figure 1B and Supplementary Figure S1A)

Summary

Introduction

According to the global cancer statistics, gastric cancer (GC) is regarded as one of the most invasive cancers and is the third leading factor of tumor-associated deaths (Bray et al, 2018). YTHDF1 (m6A “reader”) can be used to predict poor prognosis in breast cancer and promotes FDZ5 translation, leading to hepatocellular carcinoma progression (Anita et al, 2020; Liu X. et al, 2020). YTHDF1 can bind to mammalian mRNAs and alter the protein translation process in a m6A-dependent manner. It can modulate the translational efficiency of cyclin-dependent kinases in lung adenocarcinomas (Shi et al, 2019), EIF3C in ovarian cancer (Liu T. et al, 2020), and lysosomal cathepsins in melanoma and colorectal cancer (Han D. et al, 2019)

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