Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Oncogene (Impact Factor: 8.46). 06/2007; 26(24):3511-20. DOI: 10.1038/sj.onc.1210141
Source: PubMed


Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate beta-catenin/T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or beta-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signal-activated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear beta-catenin, ABI was significantly higher than in those without. These results collectively indicate that beta-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

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Available from: Masanobu Oshima, Apr 06, 2015
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    • "Because purified WNT proteins are highly unstable (Dhamdhere et al., 2014; Green et al., 2013), we reasoned that daily addition of Wnt3a protein may produce nonphysiological spikes in WNT signaling activity that may contribute to this chromosomal instability. Previous studies have linked aberrant WNT signaling to chromosomal instability (Aoki et al., 2007; Fodde et al., 2001; Hadjihannas and Behrens, 2006; Hadjihannas et al. "
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    ABSTRACT: WNT signaling promotes the reprogramming of somatic cells to an induced pluripotent state. We provide genetic evidence that WNT signaling is a requisite step during the induction of pluripotency. Fibroblasts from individuals with focal dermal hypoplasia (FDH), a rare genetic syndrome caused by mutations in the essential WNT processing enzyme PORCN, fail to reprogram with standard methods. This blockade in reprogramming is overcome by ectopic WNT signaling and PORCN overexpression, thus demonstrating that WNT signaling is essential for reprogramming. The rescue of reprogramming is critically dependent on the level of WNT signaling: steady baseline activation of the WNT pathway yields karyotypically normal iPSCs, whereas daily stimulation with Wnt3a produces FDH-iPSCs with severely abnormal karyotypes. Therefore, although WNT signaling is required for cellular reprogramming, inappropriate activation of WNT signaling induces chromosomal instability, highlighting the precarious nature of ectopic WNT activation and its tight relationship with oncogenic transformation. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; 9(5). DOI:10.1016/j.celrep.2014.10.049 · 8.36 Impact Factor
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    • "Alternatively, the CIN-inducing effect can result from the general activation of WNT signaling by CCAT2. This hypothesis is supported by previous findings that CTNNB1/TCF7L2-mediated transcription (Aoki et al. 2007) or ectopic expression of the WNT target gene conductin (AXIN2) (Hadjihannas et al. 2006) directly induce CIN. However, it should be noted that although CIN can be the underlying mechanism for CCAT2-promoted tumor growth and metastasis, mechanistic connections of these phenotypes are not established in this study. "
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    ABSTRACT: The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long non-coding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrated that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation on the SNP-conferred cancer risk.
    Genome Research 06/2013; DOI:10.1101/gr.152942.112 · 14.63 Impact Factor
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    • "APP, a protein most widely studied for its role in Alzheimer disease, has recently been identified as a component of the TIP60 DNA repair complex, a complex that modifies histone acetylation at DNA double strand breaks [40,41]. β-catenin has a key role in the activation of canonical Wnt signaling and has also recently been implicated in chromosomal instability; specifically, Aoki et al. describe defects in β-catenin leading to activation of Wnt signaling and dysregulation of the cell cycle and chromosomal instability [43]. That DDR and DNA maintenance may have a central role is also supported by the identification in the discovery phase of approximately 20 autoAbs, the antigens against which have known roles in DDR and DNA maintenance, including SWSAP1, CSNK1D, MCM10, NUDT1 and UBE2W. "
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    Orphanet Journal of Rare Diseases 03/2013; 8(1):45. DOI:10.1186/1750-1172-8-45 · 3.36 Impact Factor
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