The Role Of YTHDF1 In The Colorectal Tumorigenesis

Colorectal cancer(CRC)is one of the most common malignant tumors in humans.The initiation of CRC is affected by various genetic and epigenetic factors.The loss of stability of the genome and epigenetics will accelerate the accumulation of mutations and epigenetic changes in tumor suppressor genes and oncogenes.Recent studies have shown that RNA methylation plays a vital role during colorectal tumorigenesis.Aberrant RNA methylation may contribute to the progress of CRC.m6A methylation is one of the most abundant mRNA modifications in eukaryotic cells.YTH family proteins are the main m6A binding proteins and regulate mRNA metabolism,including mRNA splicing,degradation,and translation.Among them,m6A gene Reader,YTHDF1,mainly regulates the translation of mRNA and plays an important role in different biological processes and diseases by regulating gene expression.Studies have shown that overexpression of YTHDF1 may promote the progression of CRC and play a key role in maintaining the stemness of tumor stem cells.However,the specific role and mechanism of YTHDF1 in colorectal cancer is not yet clear.In this study,first,we found that the expression of YTHDF1 mRNA in TCGA colorectal cancer sample RNA-seq database increased significantly,and different databases and clinical samples showed that:compared with normal colorectal tissue,YTHDF1 expression in cancerous tissue significantly increased.Secondly,we proved through a series of in vivo and in vitro cell experiments:1)knockdown of YTHDF1 inhibited the proliferation,clonal formation,invasion,and migration of colorectal cancer cell lines;2)knockdown of YTHDF1 inhibits the growth of CRC xenograft.Thirdly,the preliminary exploration of the molecular mechanism shows that:1)knocking out YTHDF1 blocked the cycle of colorectal cancer cells in G1 phase,and also promotes apoptosis;2)The RNA-seq and GSEA gene enrichment analysis showed that:YTHDF1 may promote the CRC tumorigenesis by regulating cancer-related metabolism and immune response.Finally,we successfully constructed a YTHDF1 knockout mouse animal model for further in-vivo functional studies.In summary,we explored the function of YTHDF1 in CRC tumorigenesis.Our studies show that YTHDF1 is overexpressed in CRC,and inhibition of YTHDF1 expression can significantly inhibit the CRC tumorigenesis in vivo and in vitro,so the YTHDF1 plays a role in promoting tumors in CRC.At the same time,we also discovered the possible molecular mechanism for YTHDF1 to promote the development of colorectal cancer,and constructed related animal knockout models.The research in this paper paves the way for further studies of YTHDF1 function and targeted therapy in colorectal cancer.