TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex

Zimmerli, Dario; Borrelli, Costanza; Jauregi-Miguel, Amaia; Söderholm, Simon; Brütsch, Salome; Doumpas, Nikolaos; Reichmuth, Jan; Murphy-Seiler, Fabienne; Aguet, Michel; Basler, Konrad; Moor, Andreas E.; Cantù, Claudio

doi:10.7554/elife.58123

Cited by 36 publications

(37 citation statements)

References 37 publications

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“…One explanation for this observation could be that while TCF and CDX TFs directly bind to these WREs in all 3 cell types, the TF collectives regulating these WREs contain additional cell type-specific TFs which contribute to enhancer activity without binding to DNA. A similar model has been proposed for TBX3 regulation of Wnt targets in mammalian limb development (Zimmerli et al, 2020). Similarly, the addition of CAG sites increases WRE activity in LS174T and HeLa cells but decreases it in HEK293T cells.…”

Section: Discussionmentioning

confidence: 68%

Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif

Ramakrishnan

Chen

Burby

et al. 2021

Preprint

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Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been investigated in detail. We characterised a Wnt-responsive element (WRE) downstream of the Wnt target gene Axin2 and found that TCFs and Caudal-related homeodomain (CDX) proteins were required for its activation. Using a new separation-of-function TCF mutant, we found that WRE activity requires the formation of a TCF/CDX complex. Our systematic mutagenesis of this enhancer identified other sequences essential for activation by Wnt signalling, including several copies of a novel CAG DNA motif. Computational and experimental evidence indicates that the TCF/CDX/CAG mode of regulation is prevalent in multiple WREs. Put together, our results demonstrate the complex nature of cis- and trans- interactions required for signal-dependent enhancer activity.

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Section: Discussionmentioning

confidence: 68%

Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif

Ramakrishnan

Chen

Burby

et al. 2021

Preprint

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“…Furthermore, BCL9 is a cofactor that can promote the transcription of Wnt related genes, 24 which motivated us to explore whether NCK1-AS1 can regulate the activation of Wnt pathway by modulate BCL9 expression. The Wnt/β-catenin pathway is widely detected in the malignant progression of many tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, NCK1-AS1 serving as a ceRNA to positively modulated BCL9 expression by binding with miR-22-3p in gastric cancer. NCK1-AS1 activates the Wnt/β-catenin pathway via the miR-22-3p/BCL9 axis BCL9 is a β-catenin cofactor that can promote the transcription of Wnt related genes 24. Since BCL9 was directly targeted by miR-22-3p in the current study, we investigated whether the NCK1-AS1/miR-22-3p axis was responsible for the activation of the Wnt/β-catenin signaling by regulating BCL9 expression.…”

mentioning

confidence: 94%

LncRNA NCK1‐AS1 exerts oncogenic property in gastric cancer by targeting the miR‐22‐3p/BCL9 axis to activate the Wnt/β‐catenin signaling

Guan¹,

Ma²,

Yang

et al. 2021

Environmental Toxicology

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Long noncoding RNAs (lncRNAs) exert crucial effects on the development of many malignancies, including gastric cancer. Herein, we investigated the role of lncRNA noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1) divergent transcript (NCK1-DT, also known as NCK1-AS1) in gastric cancer. Reverse transcription quantitative polymerase chain reaction demonstrated that NCK1-AS1 exhibited high expression in gastric cancer tissues and cells. In vitro assays including MTT, colony formation, Transwell, wound healing and sphere formation assays indicated that NCK1-AS1 depletion inhibited cell proliferation, migration, invasion and stemness maintenance. Luciferase reporter and RIP assays suggested that NCK1-AS1 functioned as a competitive endogenous RNA (ceRNA) for miR-22-3p to positively modulate BCL9 expression. BCL9 was a target gene of miR-22-3p. According to western blot analysis and TOP/FOP flash assay, NCK1-AS1 activated the Wnt/β-catenin signaling via the miR-22-3p/BCL9 axis. Furthermore, rescue experiments verified that NCK1-AS1 affected cellular processes by activating the Wnt/β-catenin signaling pathway via the miR-22-3p/BCL9 axis. Tumor xenograft model validated that NCK1-AS1 promoted tumor growth in vivo via the Wnt/β-catenin signaling by upregulating BCL9 expression. Overall, NCK1-AS1 functions as an oncogene and promotes gastric cancer progression via the miR-22-3p/BCL9-Wnt/β-catenin signaling pathway.

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“…Conversely, the inflammatory effector protein AP-1 associates with the β-catenin transcriptional complex to activate both AP-1 and Wnt target gene expression, which drives the progression of CRC [ 40 , 41 , 42 ]. The forelimb-specific T-box transcription factor 3 (TBX3) also activates Wnt signaling by associating with the β-catenin transcriptional complex, and its aberrant expression may contribute to CRC metastasis [ 43 ]. Moreover, transcription factors can regulate Wnt signaling activity by other means.…”

Section: Wnt Signaling In Cancermentioning

confidence: 99%

Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Koch

2021

Cancers

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Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

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TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex

Cited by 36 publications

References 37 publications

Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif

Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif

LncRNA NCK1‐AS1 exerts oncogenic property in gastric cancer by targeting the miR‐22‐3p/BCL9 axis to activate the Wnt/β‐catenin signaling

Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

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