期刊
EMBO REPORTS
卷 21, 期 4, 页码 -出版社
WILEY
DOI: 10.15252/embr.201949229
关键词
intestinal stem cell; m(6)A; tumorigenesis; Wnt signaling; YTHDF1
资金
- National Natural Science Foundation of China [81672847, 81971886]
- Zhejiang Provincial Natural Science Foundation of China [LQ19C050004]
N6-methyladenosine (m(6)A) mRNA methylation has emerged as an important player in many biological processes by regulating gene expression. However, its roles in intestinal stem cell (ISC) homeostasis remain largely unknown. Here, we report that YTHDF1, an m(6)A reader, is highly expressed in ISCs and its expression is upregulated by Wnt signaling at the translational level. Whereas YTHDF1 is dispensable for normal intestinal development in mice, genetic ablation of Ythdf1 dramatically blocks Wnt-driven regeneration and tumorigenesis with reduced ISC stemness. Mechanistically, YTHDF1 facilitates the translation of Wnt signaling effectors including TCF7L2/TCF4, while this process is enhanced during Wnt activation to augment beta-catenin activity. Targeting YTHDF1 in ISCs of established tumors leads to tumor shrinkage and prolonged survival. Collectively, our studies unveil YTHDF1 as an amplifier of Wnt/beta-catenin signaling at the translational level, which is required for the maintenance of ISCs during regeneration and tumorigenesis.
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