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Gene expression in colon cancer cell lines

ABSTRACT: Genetic and epigenetic defects in Wnt/ß-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/ß-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly de-repressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/ß-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/ß-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/ß-catenin signaling in colorectal cancer. Keywords: Colon cancer cell line

ORGANISM(S): Homo sapiens

PROVIDER: GSE10952 | GEO | 2008/03/29

SECONDARY ACCESSION(S): PRJNA108791

REPOSITORIES: GEO

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Colon cancer

Project description:Genetic and epigenetic defects in Wnt/?-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/ß-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly de-repressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/?-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/ß-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/ß-catenin signaling in colorectal cancer. This SuperSeries is composed of the SubSeries listed below.

2008-03-29 | GSE10972 | GEO

Comparing gene expression in human colon tumor vs paired normal colon mucosa

Project description:24 colon normal and tumor pairs using Illumina BeadChip Human Ref8-v2. Genetic and epigenetic defects in Wnt/ß-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/ß-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly de-repressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/ß-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/ß-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/ß-catenin signaling in colorectal cancer. The clinical information for the colon tumor is not available. Keywords: human colon tumor

2008-03-29 | GSE10950 | GEO

Huwe1-mediated ubiquitylation of Dvl defines a novel negative feedback loop in the Wnt signaling pathway

Project description:Wnt signaling plays a central role in development, adult tissue homeostasis and cancer. Several steps in the canonical Wnt/b-catenin signaling cascade are regulated by ubiquitylation, a protein modification that influences the stability, subcellular localization or protein-protein interactions of target proteins. To identify novel regulators of the Wnt/b-catenin pathway, we performed RNAi screens in C. elegans and human tissue culture cells and identified the HECT domain containing ubiquitin ligase eel-1/Huwe1 as a negative regulator of Wnt signaling. Huwe1 functions cell autonomously in signal-receiving cells and genetically acts upstream of b-catenin. Mechanistically, Huwe1 binds to and ubiquitylates the cytoplasmic Wnt pathway component Dishevelled (Dvl) in a Wnt3a and CK1e dependent manner. Huwe1 mediated ubiquitylation does not target Dvl for degradation. Instead, we found that Huwe1 decreases Dvl signaling by inhibiting Dvl multimerization. We conclude that Huwe1 is part of an evolutionarily conserved negative feedback loop in the Wnt/b-catenin pathway

2014-05-28 | PXD000781 | Pride

The kinase TNIK is an essential activator of Wnt target genes

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2009-08-13 | GSE17623 | GEO

Dishevelled-3 protein conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1

Project description:Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we developed the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein Kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.

2019-04-02 | PXD013085 | Pride

Nucleoredoxin is required for the maintenance of Wnt/Î²-catenin signaling in mice embryo

Project description:We previously showed that nucleoredoxin (NRX) suppresses Wnt/Î²-catenin signaling through its binding to Dishevelled (Dvl) (Nat Cell Biol 8, 501-508 (2006)). To clarify the in vivo role of NRX in mammals, we here generate NRX gene-knockout mice (NRX-/- mice) by homologous recombination. NRX-/- mice die around birth. Therefore, we performed microarray analyses with NRX+/+ and NRX-/- embryos of E9.5 and E11.5 stages. Surprisingly, in the genes commonly upregulated at both stages, we could not observe Wnt/Î²-catenin targets. Rather, several target genes for Wnt/Î²-catenin pathway, such as Frizzled2 and Occludin, are downregulated in NRX-/- whole embryos. Frizzled2 is a gene reportedly expressed in developmental heart. Indeed, by RT-PCR analyses we confirmed that the expression of Frizzled2, as well as other Wnt/Î²-catenin target genes, was downregulated in embryonic heart of NRX-/- mice. We also found that the amount of unphosphorylated (i.e. activated) form of Î²-catenin was downregulated in NRX-/- embryonic heart. These results reveal that NRX plays another role which was unidentified in culture cell studies; it is required for the maintenance of Wnt/Î²-catenin signaling activity. Total RNAs were extracted from E9.5 and E11.5 embryos derived from NRX+/+ and NRX-/- C57BL/6J mice using RNeasy extraction kit (Qiagen). Two dye-swapped experiments were performed by hybridizing complimentary RNA (cRNA) labeled with either Cyanine (Cy) -3 or Cy-5 (Perkin-Elmer) onto Whole Mouse Genome Oligo Microarray (G4122A; Agilent Technologies). The signature genes with mean fold changes > +2.0 or < -2.0 at both stages were subjected for further evaluation.

2010-10-26 | E-GEOD-21954 | biostudies-arrayexpress

Nucleoredoxin is required for the maintenance of Wnt/β-catenin signaling in mice embryo

Project description:We previously showed that nucleoredoxin (NRX) suppresses Wnt/β-catenin signaling through its binding to Dishevelled (Dvl) (Nat Cell Biol 8, 501-508 (2006)). To clarify the in vivo role of NRX in mammals, we here generate NRX gene-knockout mice (NRX-/- mice) by homologous recombination. NRX-/- mice die around birth. Therefore, we performed microarray analyses with NRX+/+ and NRX-/- embryos of E9.5 and E11.5 stages. Surprisingly, in the genes commonly upregulated at both stages, we could not observe Wnt/β-catenin targets. Rather, several target genes for Wnt/β-catenin pathway, such as Frizzled2 and Occludin, are downregulated in NRX-/- whole embryos. Frizzled2 is a gene reportedly expressed in developmental heart. Indeed, by RT-PCR analyses we confirmed that the expression of Frizzled2, as well as other Wnt/β-catenin target genes, was downregulated in embryonic heart of NRX-/- mice. We also found that the amount of unphosphorylated (i.e. activated) form of β-catenin was downregulated in NRX-/- embryonic heart. These results reveal that NRX plays another role which was unidentified in culture cell studies; it is required for the maintenance of Wnt/β-catenin signaling activity.

2010-10-26 | GSE21954 | GEO

Comparative phosphorylation map of Dishevelled 3 links phospho-signatures to biological outputs.

Project description:Background: Dishevelled (DVL) is an essential component of the Wnt signaling cascades. Function of DVL is controlled by phosphorylation but the molecular details are missing. DVL3 contains 131 serines and threonines whose phosphorylation generates complex barcodes underlying diverse DVL3 functions. In order to dissect the role of DVL phosphorylation we analyzed the phosphorylation of human DVL3 induced by previously reported (CK1ε, NEK2, PLK1, CK2α, RIPK4, PKCδ) and newly identified (TTBK2, Aurora A) DVL kinases. Methods: Shotgun proteomics including TiO2 enrichment of phosphorylated peptides followed by liquid chromatography tandem mass spectrometry on immunoprecipitates from HEK293T cells was used to identify and quantify phosphorylation of DVL3 protein induced by 8 kinases. Functional characterization was performed by in-cell analysis of phospho-mimicking/non phosphorylatable DVL3 mutants and supported by FRET assays and NMR spectroscopy. Results: We used quantitative mass spectrometry and calculated site occupancies and quantified phosphorylation of >80 residues. Functional validation demonstrated the importance of CK1ε-induced phosphorylation of S268 and S311 for Wnt-3a-induced β-catenin activation. S630-643 cluster phosphorylation by CK1, NEK2 or TTBK2 is essential for even subcellular distribution of DVL3 when induced by CK1 and TTBK2 but not by NEK2. Further investigation showed that NEK2 utilizes a different mechanism to promote even localization of DVL3. NEK2 triggered phosphorylation of PDZ domain at S263 and S280 prevents binding of DVL terminus to PDZ and promotes an open conformation of DVL3 that is more prone to even subcellular localization. Conclusions: We identify unique phosphorylation barcodes associated with DVL function. Our data provide an example of functional synergy between phosphorylation in structured domains and unstructured IDRs that together dictate the biological outcome.

2020-01-09 | PXD015963 | Pride

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