A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis

Fang, Liang; Zhu, Qionghua; Neuenschwander, Martin; Specker, Edgar; Wulf-Goldenberg, Annika; Weis, William I.; Kries, Jens Peter von; Birchmeier, Walter

doi:10.1158/0008-5472.can-15-1519

Cited by 149 publications

(122 citation statements)

References 53 publications

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“…Of these binding factors, the transcription of the CDH1 , LEF1 and TCF7L2 genes was up-regulated in GC cells (Table 1). It has been reported that a small molecule antagonist of the β-catenin/T-cell transcription factor 4 [TCF4; official name is transcription factor 7 like 2 (TCF7L2)] interaction inhibits self-renewal of CSCs and suppresses tumorigenesis[19]. The 3D complex structures of β-catenin and TCF7L2 are available[20,21].…”

Section: Resultsmentioning

confidence: 99%

Gene expression and pathway analysis of CTNNB1 in cancer and stem cells

Tanabe¹,

Kawabata²,

Aoyagi³

et al. 2016

WJSC

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AIMTo investigate β-catenin (CTNNB1) signaling in cancer and stem cells, the gene expression and pathway were analyzed using bioinformatics.METHODSThe expression of the catenin β 1 (CTNNB1) gene, which codes for β-catenin, was analyzed in mesenchymal stem cells (MSCs) and gastric cancer (GC) cells. Beta-catenin signaling and the mutation of related proteins were also analyzed using the cBioPortal for Cancer Genomics and HOMology modeling of Complex Structure (HOMCOS) databases.RESULTSThe expression of the CTNNB1 gene was up-regulated in GC cells compared to MSCs. The expression of EPH receptor A8 (EPHA8), synovial sarcoma translocation chromosome 18 (SS18), interactor of little elongation complex ELL subunit 1 (ICE1), patched 1 (PTCH1), mutS homolog 3 (MSH3) and caspase recruitment domain family member 11 (CARD11) were also shown to be altered in GC cells in the cBioPortal for Cancer Genomics analysis. 3D complex structures were reported for E-cadherin 1 (CDH1), lymphoid enhancer binding factor 1 (LEF1), transcription factor 7 like 2 (TCF7L2) and adenomatous polyposis coli protein (APC) with β-catenin.CONCLUSIONThe results indicate that the epithelial-mesenchymal transition (EMT)-related gene CTNNB1 plays an important role in the regulation of stem cell pluripotency and cancer signaling.

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Section: Resultsmentioning

confidence: 99%

Gene expression and pathway analysis of CTNNB1 in cancer and stem cells

Tanabe¹,

Kawabata²,

Aoyagi³

et al. 2016

WJSC

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“…Additionally, SW620 spheroids exhibited increased expression of β-catenin compared to monolayers cells suggesting that TG2 and β-catenin may be necessary in cancer stem cell formation [50]. More recent studies also suggest that the self-renewal capacity of cancer stem cells in colon and head and neck cancer cells was blocked by perturbation of the interaction between β-catenin and the transcription factor TCF4 in the nucleus [52]. This supports our current notion in SW620 cells where TG2 plays a role in inhibiting β-catenin ubiquitination and thus facilitates accumulation of β-catenin in the nucleus where it can interact with TCF4, enhancing the self-renewal and enhancing cancer stem cell capacity, a process that can be perturbed by inhibiting TG2.…”

Section: Discussionmentioning

confidence: 99%

Tissue transglutaminase induces Epithelial-Mesenchymal-Transition and the acquisition of stem cell like characteristics in colorectal cancer cells

2017

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Human colon cancer cell lines (CRCs) RKO, SW480 and SW620 were investigated for TG2 involvement in tumour advancement and aggression. TG2 expression correlated with tumour advancement and expression of markers of epithelial-mesenchymal transition (EMT). The metastatic cell line SW620 showed high TG2 expression compared to the primary tumour cell lines SW480 and RKO and could form tumour spheroids under non- adherent conditions. TG2 manipulation in the CRCs by shRNA or TG2 transduction confirmed the relationship between TG2 and EMT. TGFβ1 expression in CRC cells, and its level in the cell medium and extracellular matrix was increased in primary tumour CRCs overexpressing TG2 and could regulate TG2 expression and EMT by both canonical (RKO) and non-canonical (RKO and SW480) signalling. TGFβ1 regulation was not observed in the metastatic SW620 cell line, but TG2 knockdown or inhibition in SW620 reversed EMT. In SW620, TG2 expression and EMT was associated with increased presence of nuclear β-catenin which could be mediated by association of TG2 with the Wnt signalling co-receptor LRP5. TG2 inhibition/knockdown increased interaction between β-catenin and ubiquitin shown by co-immunoprecipitation, suggesting that TG2 could be important in β-catenin regulation. β-Catenin and TG2 was also upregulated in SW620 spheroid cells enriched with cancer stem cell marker CD44 and TG2 inhibition/knockdown reduced the spheroid forming potential of SW620 cells. Our data suggests that TG2 could hold both prognostic and therapeutic significance in colon cancer.

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“…MTT assays were performed using MTT solution (Sigma-Aldrich) and processed according to the manufacturer’s instructions and Stat Fax 2100 ELISA reader. Colony and sphere formation were performed similar to that described in Staller et al (2001) and Fang et al (2016).…”

Section: Methodsmentioning

confidence: 99%

RNF4-Dependent Oncogene Activation by Protein Stabilization

et al. 2016

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SUMMARYUbiquitylation regulates signaling pathways critical for cancer development and, in many cases, targets proteins for degradation. Here, we report that ubiquitylation by RNF4 stabilizes otherwise short-lived oncogenic transcription factors, including β-catenin, Myc, c-Jun, and the Notch intracellular-domain (N-ICD) protein. RNF4 enhances the transcriptional activity of these factors, as well as Wnt- and Notch-dependent gene expression. While RNF4 is a SUMO-targeted ubiquitin ligase, protein stabilization requires the substrate’s phosphorylation, rather than SUMOylation, and binding to RNF4’s arginine-rich motif domain. Stabilization also involves generation of unusual polyubiquitin chains and docking of RNF4 to chromatin. Biologically, RNF4 enhances the tumor phenotype and is essential for cancer cell survival. High levels of RNF4 mRNA correlate with poor survival of a subgroup of breast cancer patients, and RNF4 protein levels are elevated in 30% of human colon adenocarcinomas. Thus, RNF4-dependent ubiquitylation translates transient phosphorylation signal(s) into long-term protein stabilization, resulting in enhanced oncoprotein activation.

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A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis

Cited by 149 publications

References 53 publications

Gene expression and pathway analysis of CTNNB1 in cancer and stem cells

Gene expression and pathway analysis of CTNNB1 in cancer and stem cells

Tissue transglutaminase induces Epithelial-Mesenchymal-Transition and the acquisition of stem cell like characteristics in colorectal cancer cells

RNF4-Dependent Oncogene Activation by Protein Stabilization

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