YTHDF1 Amplifies Wnt/ß-Catenin Signaling to Promote Intestinal Stemness

Wnt/ß-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating ß-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment ß-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy. Overall design: Investigating YTHDF1-regulated mRNA translation in HCT116 cells Please note that the indiviual_ribosome_rna_profile.txt pcontains the processed data for GSM4054749-GSM4054754 samples and is linked to the GSM4054749 sample records.