Multilevel regulation of Wnt signaling by Zic2 in colon cancer due to mutation of β-catenin
Autor: | Jianbao Zheng, Zilu Chen, Junhui Yu, Chao Qu, Jing Guo, Chen Cheng, Liyue Yuan, Xuejun Sun, Xingjie Wang, Zhengshui Xu, Xiaopeng Li |
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Rok vydání: | 2021 |
Předmět: |
Cancer Research
Colorectal cancer Immunology Mice Nude Biology Transfection medicine.disease_cause Article Mice Cell growth Cellular and Molecular Neuroscience AXIN2 medicine Animals Humans Gene silencing Wnt Signaling Pathway beta Catenin QH573-671 Wnt signaling pathway Nuclear Proteins Cell Biology Cell cycle medicine.disease Colon cancer Catenin Colonic Neoplasms Cancer research Ectopic expression Cytology Carcinogenesis Transcription Factors |
Zdroj: | Cell Death and Disease, Vol 12, Iss 6, Pp 1-13 (2021) Cell Death & Disease |
ISSN: | 2041-4889 |
Popis: | Zinc-finger of the cerebellum 2 (Zic2) is widely implicated in cancers, but the role of Zic2 in tumorigenesis is bilateral. A recent study indicated that Zic2 could render colon cancer cells more resistant to low glucose-induced apoptosis. However, the functional roles of Zic2 in colon cancer and the underlying molecular mechanism remain elusive. Herein, we demonstrated that Zic2 was highly expressed in colon cancer tissues and correlated with poor survival. Knockdown of Zic2 inhibited colon cancer cell growth, arrested the cell cycle transition from G0/G1 to S phase, and suppressed tumor sphere formation in vitro; in addition, silencing Zic2 retarded xenograft tumor formation in vivo. Consistently, ectopic expression of Zic2 had the opposite effects. Mechanistically, Zic2 executed its oncogenic role in colon cancer by enhancing Wnt/β-catenin signaling. Zic2 directly binds to the promoter of Axin2 and transcriptionally represses Axin2 expression and subsequently promotes the accumulation and nuclear translocation of β-catenin. Meanwhile, Zic2 could activate Wnt signaling by interacting with β-catenin. Intriguingly, in HCT116 cells with intrinsic Ser45 mutation of β-catenin, which blocks the degradation-related phosphorylation of β-catenin by CK1, modified Zic2 expression did not affect the protein level of β-catenin. Altogether, our findings uncover a novel multilevel mechanism for the oncogenic activity of Zic2 in colon cancer and suggest Zic2 as a potential therapeutic target for colon cancer patients. |
Databáze: | OpenAIRE |
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