FOXP4-mediated induction of PTK7 activates the Wnt/β-catenin pathway and promotes ovarian cancer development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1013114 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25918414_1.fastq.gz | Fastqsanger.gz | |||
| SRR25918414_2.fastq.gz | Fastqsanger.gz | |||
| SRR25918415_1.fastq.gz | Fastqsanger.gz | |||
| SRR25918415_2.fastq.gz | Fastqsanger.gz | |||
| SRR25918416_1.fastq.gz | Fastqsanger.gz |
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Project description:Ovarian cancer (OC) presents a significant challenge in clinical settings due to its difficulty in early diagnosis and its resistance to treatment. FOXP4 is a member of the FOXP subfamily and is involved in various biological processes including embryonic development, cell cycle regulation, and tumorigenesis. Despite its potential role in cancer, the exact function and significance of FOXP4 in OC remain uncertain. Here we showed that FOXP4 was expressed at high levels in OC, and its high expression was associated with poor prognosis. Furthermore, RNA sequencing and functional analysis of cells lacking FOXP4 suggest that FOXP4 contributes to the activation of the Wnt signaling pathway, leading to the amplification of the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, leading to abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OC cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings highlight the importance of FOXP4 in the activation of the Wnt signaling pathway in OC and provide evidence for the potential therapeutic value of targeting this pathway in the treatment of the disease.
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2018-12-27 | GSE124339 | GEO
Project description:The canonical Wnt/β-catenin signaling pathway plays multiple roles during Xenopus gastrulation, including posteriorization of the neural plate, patterning of the mesoderm, and induction of the neural crest. Wnt signaling stabilizes β-catenin, which then activates target genes. However, few targets of this signaling pathway that mediate early developmental processes are known. Here we sought to identify transcriptional targets of the Wnt/β-catenin signaling pathway using a genome-wide approach.
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Project description:Colorectal cancer (CRC) ranks second in cancer-related mortality worldwide, with clinical intractability and chemoresistance representing significant challenges driven by cancer stem cells (CSCs). Wnt/β-catenin signaling is a lynchpin of CSC self-renewal, but targetable upstream drivers remain elusive. Using bioinformatics we identified the proteoglycan SPOCK1 as a Wnt-associated CSC target. Critically, high SPOCK1 expression predicted poor patient prognosis and reduced progression-free survival following first-line chemotherapy. In vitro assays demonstrated that SPOCK1 levels modulated Wnt/β-catenin activity. SPOCK1 silencing inhibited β-catenin nuclear translocation and TCF/LEF-mediated transcription, which concurrently suppressed CRC proliferation and stemness. Conversely, SPOCK1 overexpression promoted β-catenin nuclear translocation and TCF/LEF-mediated transcription, which enhanced CRC proliferation and stemness. This SPOCK1-driven pro-tumorigenic effect was significantly reversed by the β-catenin/TCF/LEF inhibitor iCRT3, demonstrating SPOCK1’s dependence on Wnt transcriptional activation. The functional role was validated in vivo using a SPOCK1-overexpressing xenograft model and ex vivo using patient-derived organoids (PDOs), both confirming increased growth and β-catenin nuclear localization. Furthermore, data-independent acquisition (DIA) mass spectrometry of SPOCK1-overexpressing tumors revealed pro-tumorigenic signaling including c-Myc activity, oxidative phosphorylation, epithelial-mesenchymal transition. Notably, SPOCK1 drove remodeling of the tumor microenvironment, characterized by desmoplasia and fibrosis. Overall, our findings establish a SPOCK1/Wnt/β-catenin axis as a novel mechanism driving CRC tumorigenesis and stemness, positioning it as a promising therapeutic target to overcome Wnt-mediated progression and resistance.
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Project description:The Wnt/β-catenin signaling pathway is a critical regulator of development and stem cell maintenance. Mounting evidence suggests that the context-specific outcome of Wnt signaling is determined by the collaborative action of multiple transcription factors, including members of the highly conserved forkhead box (FOX) protein family. The contribution of FOX transcription factors to Wnt signaling has not been investigated in a systemic manner. Here, by combining β-catenin reporter assays with Wnt pathway-focused qPCR arrays and proximity proteomics of selected FOX family members, we determine that most FOX proteins are involved in the regulation of Wnt pathway activity and the expression of Wnt ligands and target genes. We conclude that FOX proteins are common regulators of the Wnt/β-catenin pathway that may control the outcome of Wnt signaling in a tissue-specific manner.
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Project description:Purpose: Combination of systemic RNAi with RNAseq to identify target genes of important pathways in early development Wnt/β-catenin and hedgehog (Hh) signaling are essential for transmitting signals across cell membranes in animal embryos. Early patterning of the principal insect model, Drosophila melanogaster, occurs in the syncytial blastoderm, where diffusion of transcription factors obviates the need for signaling pathways. However, in the cellularized growth zone of typical short germ insect embryos, signaling pathways are predicted to play a more fundamental role. Indeed, the Wnt/β-catenin pathway is required for posterior elongation in most arthropods, although which target genes are activated in this context remains elusive. Here, we use the short germ beetle Tribolium castaneum to investigate two Wnt and Hh signaling centers located in the head anlagen and in the growth zone of early embryos. We find that Wnt/β-catenin signaling acts upstream of Hh in the growth zone, whereas the opposite interaction occurs in the head. We determine the target gene sets of the Wnt/β-catenin and Hh pathways and find that the growth zone signaling center activates a much greater number of genes and that the Wnt and Hh target gene sets are essentially non-overlapping. The Wnt pathway activates key genes of all three germ layers, including pair-rule genes, and Tc-caudal and Tc-twist. Furthermore, the Wnt pathway is required for hindgut development and we identify Tc-senseless as a novel hindgut patterning gene required in the early growth zone. At the same time, Wnt acts on growth zone metabolism and cell division, thereby integrating growth with patterning. Posterior Hh signaling activates several genes potentially involved in a proteinase cascade of unknown function.
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2021-03-05 | PXD021181 | Pride
Project description:SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes displace nucleosomes to promote the access of transcription factors to enhancers and promoters. Despite the critical roles of SWI/SNF in animal development and tumorigenesis, how signaling pathways recruit SWI/SNF complexes to their target genes is unclear. Here, we demonstrate that target gene activation mediated by Beta-catenin, the essential transcriptional coactivator in the Wnt signal transduction pathway, requires ubiquitylation of the SWI/SNF component Brahma-related gene-1 (BRG1) by the E3 ubiquitin ligase Thyroid Hormone Receptor Interactor 12 (TRIP12). TRIP12 depletion in Drosophila, zebrafish, mouse organoids, and human cells attenuates Wnt signaling. Genetic epistasis experiments place TRIP12 activity downstream of the Beta-catenin destruction complex. TRIP12 interacts with and ubiquitylates BRG1, and BRG1 depletion blocks TRIP12-mediated Wnt pathway activation. TRIP12 promotes BRG1 binding to Beta-catenin in the presence of Wnt. Our findings support a model in which TRIP12 ubiquitylates BRG1 in the presence of Wnt and promotes its interaction with Beta-catenin, thereby bringing SWI/SNF to Wnt target genes. Our studies suggest a general mechanism by which cell signaling induces the interaction between BRG1 and pathway-specific transcription factors to recruit SWI/SNF complexes to their appropriate target genes.
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2021-09-09 | PXD020783 | Pride