Heterogeneous activation of Wnt/β-catenin signaling in prostate cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593270 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10582641_1.fastq.gz | Fastqsanger.gz | |||
| SRR10582641_2.fastq.gz | Fastqsanger.gz | |||
| SRR10582642_1.fastq.gz | Fastqsanger.gz | |||
| SRR10582642_2.fastq.gz | Fastqsanger.gz | |||
| SRR10582643_1.fastq.gz | Fastqsanger.gz |
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Project description:To study the heterogeneous activation of Wnt/β-catenin signaling in prostate cancer, we established a Wnt/β-catenin signaling reporting system 7xTCF-EGFP. We then sorted out GFP+ cells and GFP- cells and compared their properties on both molecular and cellular levels.
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Project description:Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective new approach to treating prostate cancer. Here we provide proof-of-concept that a small molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/TCF and β-catenin/AR protein interaction, reflecting the fact that TCF and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, CARM1, providing new insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model, and blocked renewal of bicalutamide-resistant sphere forming cells, indicating the therapeutic potential of this approach. Compare and contrast the expression profile of prostate cancer cells treated with a Wnt inhibitor (C3) with respect to β-catenin and AR knockdown (all samples in duplicates).
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Project description:Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we investigated aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of b-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized b-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/b-catenin in combination with short polyQ AR expression in prostate tumorigenesis and provide mechanistic insight into aggressive prostatic tumor development that is frequently observed in African American patients.
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Project description:Abberant expression and protein localization of ESM1 were found in prostate cancer. The high expression of ESM1 is associated with prostate cancer stemness and progression. Thus, ESM1 is clinically relevant to poor overall survival and metastasis. However, the molecular mechanisms by which ESM1 contribute to prostate cancer is not yet understood. To discover the role of ESM1 mislocalization in prostate cancer, RNA-seq analysis was performed on 22Rv1 cells overexpressing with different ESM1. Our study demonstrate that nuclear ESM1 may support prostate cancer stemness by interacting with the ARM domain of β-catenin to stabilize β-catenin-Tcf4 complex and facilitate the transactivation of Wnt/β-catenin signaling targets. Our results establish the significance of ESM1 in driving metastasis in prostate cancer by coordinating the Wnt/β-catenin pathway, with implication for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in prostate cancer.
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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:Aortic valve stenosis (AVS) is a prevailing and life-threatening cardiovascular disease in adults over 75 years of age. However, the molecular mechanisms governing the pathogenesis of AVS are yet to be fully unraveled. With accumulating evidence that Wnt signaling plays a key role in the development of AVS, the involvement of intracellular Wnt molecules has become an integral study target in AVS pathogenesis. Thus, we hypothesized that the Wnt/β‐catenin pathway Wnt intracellular mediators, SFRP2, DVL2, GSK3β and β‐catenin are dysregulated in patients with AVS. Using immunohistochemistry, Real‐Time qPCR and Western blotting, we investigated the presence of SFRP2, GSK‐3β, DVL2 and β‐catenin in normal and stenotic human aortic valves. Markedly higher mRNA and protein expression of GSK‐3β, DVL2, β‐catenin and SFRP2 were found in stenotic aortic valves. This was further corroborated by observation of their abundant immunostaining, which displayed strong immunoreactivity in diseased aortic valves. Proteomic analyses of selective GSK3b inhibition in calcifying human aortic valve interstitial cells (HAVICs) revealed enrichment of proteins involved organophosphate metabolism, while reducing the activation of pathogenic biomolecular processes. Lastly, use of the potent calcification inhibitor, Fetuin A, in calcifying HAVICs significantly reduced the expression of Wnt signaling genes Wnt3a, Wnt5a, Wnt5b and Wnt11. The current findings of altered expression of canonical Wnt signaling in AVS suggest a possible role for regulatory Wnts in AVS. Hence, future studies focused on targeting these molecules are warranted to underline their role in the pathogenesis of the disease.
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Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.
2018-02-07 | PXD007909 | 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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