Functions And Mechanisms Of RNA M6A Methylation Reader YTHDF1 In Promoting Hepatobiliary Malignancies Via Post-Transcriptional Regulation

Hepatobiliary malignancies were a majority group of gastrointestinal malignancies.They became significant issues of public sanitation regarding the poor prognosis.In primary hepatic malignancies,hepatocellular carcinoma was a top ranking cancer worldwide.In biliary malignanies,the most common type was gallbladder cancer.These malignancies were commonly developing occultly and patients lost chance of treatment.Therefore,the researches on early diagnosis and treatment target has become an urgent issue.RNA m6A modification was the most common RNA epigenetic modifications.Researches emerged that m6A participates in progression of multiple solid tumors.YTHDF1,as one of the major m6A reader,promotes mRNA translation and stability via binding to 5'-UTR or 3'-UTR of mRNA and recruiting eIFs or RNA stability-related proteins.We proved that YTHDF1 was upregulated in liver cancer cohort(TCGA-LIHC and ICGC-LICA-JP2)or biliary tract cancer cohorts(TCGA-CHOL).Patients with higher YTHDF1 expression tend to have poor overall surivival.Meanwhile,combined with TCGA clinicald ata,we proved that TNM stage(HR=1.469,95%CI=1.243-1.735,p<0.0001)and YTHDF1(HR=1.064,95%CI=1.007-1.123,p<0.05)as independent risk factors for poor OS of HCC patients.In this research,we proved YTHDF 1 was capable of promoting gallbladder cancer progression.YTHDF 1 promotes the growth in both gallbladder cancer cell-line NOZ and xenograft nude mice model.According to the result of RNA-seq and m6A-seq,we figured out that YTHDF1 may regulates MAPK signal pathway,cell growth and metastasis,and chromatin&DNA regulation pathways.YTHDF 1 bound to the 3'-UTR of UHRF1 mRNA,and upregulated UHRF1 by increasing the mRNA stability in an m6A-dependent manner.Co-IP analysis of YTHDF 1 proved that YTHDF 1 was bound to PABPC1 and PABPC4 proteins,which was previously proved to regulate the mRNA stability.However,whether YTHDF 1 increased UHRF1 mRNA was dependent of PABPC1 or PABPC4 or not was not clear and more researches should be performed.