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UHRF2 promotes intestinal tumorigenesis through stabilization of TCF4 mediated Wnt/β‐catenin signaling
Author(s) -
Li Liang,
Duan Qiuhui,
Zeng Zhiyang,
Zhao Jindong,
Lu Jiawei,
Sun Jialiang,
Zhang Jiqin,
Siwko Stefan,
Wong Jiemin,
Shi Tieliu,
Zhang Xueli,
Liu Mingyao,
Chen Jinlian,
Li Dali
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33036
Subject(s) - wnt signaling pathway , carcinogenesis , biology , beta catenin , catenin , downregulation and upregulation , stem cell , microbiology and biotechnology , wnt3a , lrp6 , signal transduction , adenomatous polyposis coli , cancer research , colorectal cancer , cancer , gene , genetics
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.