YTHDF1-mediated translation amplifies Wnt-driven intestinal stemness

被引：94

作者：

Han, Bing ^{[1
]}

Yan, Sujun ^{[1
]}

Wei, Saisai ^{[1
]}

Xiang, Jie ^{[1
]}

Liu, Kangli ^{[1
]}

Chen, Zhanghui ^{[2
]}

Bai, Rongpan ^{[3
]}

Sheng, Jinghao ^{[3
]}

Xu, Zhengping ^{[3
]}

Gao, Xiangwei ^{[1
,3
]}

机构：

[1] Zhejiang Univ, Sch Med, Inst Environm Med, Sir Run Run Shaw Hosp, Hangzhou, Peoples R China

[2] Guangdong Med Univ, Affiliated Hosp, Zhanjiang, Peoples R China

[3] Zhejiang Univ, Sch Med, Bioelectromagnet Lab Zhejiang Prov, Hangzhou, Peoples R China

来源：

EMBO REPORTS | 2020年 / 21卷 / 04期

基金：

中国国家自然科学基金;

关键词：

intestinal stem cell; m(6)A; tumorigenesis; Wnt signaling; YTHDF1; MESSENGER-RNA METHYLATION; BETA-CATENIN; COLON-CANCER; NUCLEAR-RNA; REGENERATION; COMPLEX; N6-METHYLADENOSINE; ACTIVATION; SUBUNIT; REVEALS;

D O I：

10.15252/embr.201949229

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：14

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