SFRPs Are Biphasic Modulators of Wnt Signaling-elicited Cancer Stem Cell Properties beyond Extracellular Control
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE133943 | GEO | 2019/07/09
REPOSITORIES: GEO
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Project description:Wnt signaling contributes to the reprogramming and maintenance of cancer stem cell (CSC) states that is activated by the epithelial-mesenchymal transition (EMT) program. However, the mechanistic relationship between the EMT and Wnt pathway in CSCs remains unclear. Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) indicated that EMT induces a switch from the β-catenin/E-cadherin/Sox15 complex to the β-catenin/Twist1/TCF4 complex, which then binds to CSC-related gene promoters. In tandem co-IP and re-ChIP experiments using epithelial-type cells, Sox15 associated with the β-catenin/E-cadherin complex and then bound to the proximal promoter region of CASP3, consequently resulting in Twist1 cleavage and negatively regulating the β-catenin–elicited promotion of the CSC phenotype. During the EMT, Twist1 in complex with β-catenin enhanced β-catenin/TCF4 transcriptional activity, which includes binding to the proximal promoter region of ABCG2, a marker of CSCs. For clinical application, the five-gene signature nuclear β-cateninHigh/nuclear Twist1High/E-cadherinLow/Sox15Low/CD133High may be a valuable prognostic marker in patients with human lung cancer.
2015-04-04 | GSE67571 | GEO
Project description:Canonical Wnt signaling output is mediated by β-catenin, which interacts with LEF/TCF transcription factors and recruits a general transcriptional activation complex to its C-terminus. Its N-terminus binds BCL9/9L proteins, which bind co-activators that in mammals contribute to fine-tuning the transcriptional output. We found that a BCL9/9L-dependent gene expression signature was strongly associated with patient outcome in colorectal cancer and that stem cell and mesenchymal genes determine its prognostic value. Abrogating BCL9/9L-β-catenin signaling in independent mouse colorectal cancer models resulted in virtual loss of these traits, and oncogenic intestinal organoids lacking BCL9/9L proteins proved no longer tumorigenic. Our findings suggest that the BCL9/9L arm of Wnt-β-catenin signaling sustains a stemness-to-differentiation equilibrium in colorectal cancer, which critically affects disease outcome. Mutational activation of the Wnt pathway is a key oncogenic event in colorectal cancer. Targeting the pathway downstream of activating mutations is challenging, and the therapeutic window is limited by intestinal toxicity. Contrasting with phenotypes caused by inactivating key Wnt pathway components, ablation of BCL9/9L proteins in adult mice indicated that they were dispensable for intestinal homeostasis, consistent with their role in tuning transcription. Cancer stem cells are increasingly recognized as responsible for tumor recurrence. The correlation between stemness traits in colorectal cancer models and BCL9/9L-β-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-β-catenin signaling might be well tolerated and prove sufficient for trimming stemness traits and improving disease outcome.
2015-11-08 | GSE60837 | GEO
Project description:To determine the critical mediator of TRIB3-enhanced Wnt/beta-catenin signaling, we examined the expression profile of genes that might regulate Wnt/beta-catenin by using mRNA microarrays. Aberrant activation of Wnt/beta-catenin signaling pathway is a major reason for the tumorigenesis of Colon cancer. However, no specific drug targeting this pathway has been in the market. Surgery combined with cytotoxic drugs are still the major therapy methods toward colon cancer. These highlighted the need for therapeutics with alternative mechanisms of action. Here we report that the elevated TRIB3 expression associates positively with Wnt/beta-catenin signaling pathway. TRIB3 interacts with beta-catenin and TCF4 to enhance the associations between TCF4/beta-catenin target genes’ promoters, which upregulates the transcriptional activity of beta-catenin, thus to promote the CSC stemness and colon cancer tumorigenesis.
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Project description:Transgenic mouse line called alphaA-CLEF in which transactivation domain of beta-catenin is fused to the amino terminus of DNA-binding protein LEF and the expression of transgenic protein is controlled by alphaA-crystallin promoter (-342/+49) was used to mimic the activation of canonical Wnt/beta-catenin signaling in lens fiber cells. The aim of this experiment was to compare the mRNA expression in wild type and transgenic (CLEF) P1-P3 lenses and reveal the differentially expressed genes.
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Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248084 | GEO
Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248083 | GEO
Project description:Canonical Wnt signaling output is mediated by β-catenin, which interacts with LEF/TCF transcription factors and recruits a general transcriptional activation complex to its C-terminus. Its N-terminus binds BCL9/9L proteins, which bind co-activators that in mammals contribute to fine-tuning the transcriptional output. We found that a BCL9/9L-dependent gene expression signature was strongly associated with patient outcome in colorectal cancer and that stem cell and mesenchymal genes determine its prognostic value. Abrogating BCL9/9L-β-catenin signaling in independent mouse colorectal cancer models resulted in virtual loss of these traits, and oncogenic intestinal organoids lacking BCL9/9L proteins proved no longer tumorigenic. Our findings suggest that the BCL9/9L arm of Wnt-β-catenin signaling sustains a stemness-to-differentiation equilibrium in colorectal cancer, which critically affects disease outcome. Mutational activation of the Wnt pathway is a key oncogenic event in colorectal cancer. Targeting the pathway downstream of activating mutations is challenging, and the therapeutic window is limited by intestinal toxicity. Contrasting with phenotypes caused by inactivating key Wnt pathway components, ablation of BCL9/9L proteins in adult mice indicated that they were dispensable for intestinal homeostasis, consistent with their role in tuning transcription. Cancer stem cells are increasingly recognized as responsible for tumor recurrence. The correlation between stemness traits in colorectal cancer models and BCL9/9L-β-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-β-catenin signaling might be well tolerated and prove sufficient for trimming stemness traits and improving disease outcome. Examination of Bcl9/9l-knockout versus wild-type transcriptome in murine AOM-DSS tumors, APC-Kras tumors and healthy colocyte extracts.
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Project description:Tiki antagonizes Wnt3a signaling by cleaving and inactivating Wnt3a in Wnt-producing cells. Tiki also functions in Wnt-receiving cells to antagonize Wnt signaling by an unknown mechanism. Here, we demonstrate that Tiki inhibition of Wnt signaling at the cell surface requires Frizzled receptors. Tiki associates with the Wnt-FZD complex and cleaves the N-terminus of Wnt3a or Wnt5a, preventing the Wnt-FZD complex from recruiting and activating the coreceptor LRP6 or ROR1/2 without affecting Wnt-FZD complex stability. Intriguingly, we demonstrate that the N-terminus of Wnt3a is required for Wnt3a binding to LRP6 and activating β-catenin signaling, while the N-terminus of Wnt5a is dispensable for recruiting and phosphorylating ROR1/2. Both Tiki enzymatic activity and its association with the Wnt-FZD complex contribute to its inhibitory function on Wnt5a. Our study uncovers the mechanism by which Tiki antagonizes Wnt signaling at the cell surface and reveals a negative role of FZDs in Wnt signaling by acting as Tiki cofactors. Our findings also reveal an unexpected role of the Wnt3a N-terminus in the engagement of the coreceptor LRP6.
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Project description:Canonical Wnt/β-catenin signalling is an essential regulator of various cellular functions throughout development and adulthood. Aberrant Wnt/β-catenin signalling also contributes to various pathologies including cancer, necessitating an understanding of cell context dependent mechanisms regulating this pathway. Since protein-protein interactions underpin β-catenin function and localization, we sought to identify novel β-catenin interacting partners by affinity purification coupled with tandem mass spectrometry in vascular smooth muscle cells (VSMCs), where β-catenin is involved in both physiological and pathological control of cell proliferation. Here, we report novel components of the VSMC β-catenin interactome.
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Project description:Canonical Wnt/B-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no β-catenin nuclear-localization even where cytosolic B-catenin is abundant. Differential propensity for nuclear-localized β-catenin is also observed in cell lines. To investigate the factors mediating the nuclear-localization of B-catenin we carried out a nuclear/cytoplasmic proteomic analysis of the B-catenin interactome in myeloid leukemia cells. From this we identified hundreds of putative novel B-catenin-interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear B-catenin, K562/HEL) versus Wnt-unresponsive cells (low nuclear B-catenin, ML1) suggested the established interactor, LEF1, is a key factor mediating the nuclear-localization of B-catenin in myeloid leukemia. The relative levels of nuclear LEF1 and B-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF1 knockdown inhibited B-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF1 overexpression was able to promote both nuclear-localization and B-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This study is the first to present a B-catenin interactome in hematopoietic cells and reveals LEF1 as a critical regulator of canonical Wnt signaling in myeloid leukemia.
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