Wnt信号通路
癌变
生物
连环蛋白
连环素
下调和上调
干细胞
细胞生物学
WNT3A型
LRP6型
信号转导
大肠腺瘤性息肉病
癌症研究
结直肠癌
癌症
基因
遗传学
作者
Liang Li,Qiuhui Duan,Zhiyang Zeng,Jindong Zhao,Jiawei Lu,Jialiang Sun,Jiqin Zhang,Stefan Siwko,Jiemin Wong,Tieliu Shi,Xueli Zhang,Mingyao Liu,Jinlian Chen,Dali Li
摘要
Abstract Intestinal tumors mainly originate from transformed crypt stem cells supported by Wnt signaling, which functions through downstream critical factors enriched in the intestinal stem/progenitor compartment. Here, we show Uhrf2 is predominantly expressed in intestinal crypts and adenomas in mice and is transcriptionally regulated by Wnt signaling. Upregulated UHRF2 correlates with poor prognosis in colorectal cancer patients. Although loss of Uhrf2 did not affect intestinal homeostasis and regeneration, tumor initiation and progression were inhibited, leading to a markedly prolonged life span in Uhrf2 null mice on an Apc Min background. Uhrf2 deficiency also strongly reduced primary tumor organoid formation suggesting impairment of tumor stem cells. Moreover, ablation of Uhrf2 suppressed tumor cell proliferation through downregulation of the Wnt/β‐catenin pathway. Mechanistically, Uhrf2 directly interacts with and sumoylates Tcf4, a critical intranuclear effector of the Wnt pathway. Uhrf2 mediated SUMOylation stabilized Tcf4 and further sustained hyperactive Wnt signaling. Together, we demonstrate that Wnt‐induced Uhrf2 expression promotes tumorigenesis through modulation of the stability of Tcf4 for maintaining oncogenic Wnt/β‐catenin signaling. This is a new reciprocal feedforward regulation between Uhrf2 and Wnt signaling in tumor initiation and progression.
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