Abstract
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.
Highlights
Colorectal cancer (CRC) is the second most prevalent cancer and the fourth leading cause of cancer-related lethality globally[1]
We found that Zic[2] transcript levels were higher in all six colon cancer cell lines than in human colonic epithelial cell line (HCoEpiC)
We found that the nuclear localization of β-catenin was unchanged in the HCT116-Zic[2] cell line, but it was markedly increased in response to ectopic expression of Zic[2] in the DLD-1 and SW480 cell lines (Fig. 4d, j)
Summary
Colorectal cancer (CRC) is the second most prevalent cancer and the fourth leading cause of cancer-related lethality globally[1]. 90% of CRCs have abnormal Wnt signaling activation, which plays important role in cancer stem cell (CSC) biology, tumorigenesis, and metastasis in CRC2–5. The disruption of the β-catenin destruction complex, consisting of CK17,8, GSK-3β9,10, Axin[7,11], and APC10,12, results in the activation of Wnt signaling. Zic[2] functions in tumorigenesis[26], cancer stem cell renewal[21], proliferation[27,28,29,30,31], invasion, and metastasis[28,30,32]. In CRC, only one Zic2-related study has been published, in which Zhao et al reported that Zic[2] can render colon cancer cells more resistant to low-glucose-induced apoptosis[31]. How Zic[2] regulates CRC tumorigenesis and progression remains elusive
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