Expression data from Control or TRIB3-silenced HCT-8 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE107094 | GEO | 2020/11/17
REPOSITORIES: GEO
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Project description:The Wnt/β-catenin pathway plays multiple/diverse roles in development by regulating gene expression via Tcf/Lef DNA binding factors. Misregulation of this pathway is thought to initiate colon adenoma formation. It is controversial whether Tcf4 (Tcf7L2) functions as an oncogene or tumor suppressor gene in colon carcinogenesis. We show here that Tcf4 haploinsufficiency results in colon tumor formation in a mouse tumor model that normally only develops small intestinal tumors. Further, we show that loss of Tcf4 early in development and in adult colon results in increased cell proliferation. These findings strongly suggest that Tcf4 normally modulates proliferation of the colonic epithelium and that disruption of Tcf4 activity increases proliferation leading to colon tumorigenesis. Taken together our in vivo studies favor a tumor suppressor function for Tcf4.
2011-03-15 | GSE27522 | GEO
Project description:The Wnt/M-NM-2-catenin pathway plays multiple/diverse roles in development by regulating gene expression via Tcf/Lef DNA binding factors. Misregulation of this pathway is thought to initiate colon adenoma formation. It is controversial whether Tcf4 (Tcf7L2) functions as an oncogene or tumor suppressor gene in colon carcinogenesis. We show here that Tcf4 haploinsufficiency results in colon tumor formation in a mouse tumor model that normally only develops small intestinal tumors. Further, we show that loss of Tcf4 early in development and in adult colon results in increased cell proliferation. These findings strongly suggest that Tcf4 normally modulates proliferation of the colonic epithelium and that disruption of Tcf4 activity increases proliferation leading to colon tumorigenesis. Taken together our in vivo studies favor a tumor suppressor function for Tcf4. 4 Normal Colon and 4 colon tumor from independent mouse tissue samples
2011-03-15 | E-GEOD-27522 | biostudies-arrayexpress
Project description:β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation. In vivo liver samples in 4 conditions: Betacat activated (WCE, Tcf4 chipseq, Betacat chipseq, mRNAseq with 2 replicates), Betacat null (WCE, Tcf4 chipseq, mRNAseq with 2 replicates), Betacat control (mRNAseq with 2 replicates), Wild type (mRNAseq with 2 replicates)
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Project description:Wnt/beta-catenin signaling is essential for stem cell regulation and cancer formation by activation of target genes transcription. For transcriptional activation, the histone around promoters needs to be modified to remove transcriptional repressors; however, the underlying mechanisms remain largely unknown. Here, we report that Wnt signal erases TCF4-associated H3K9me2/me3 by recruitment of KDM4C through β-catenin to activate gene transcription. In the absence of Wnt3a, PKR phosphorylates KDM4C which induces its ubiquitination and degradation. Wnt3a stabilizes KDM4C through inhibition of GSK3-dependent PKR kinase activity. Stabilized KDM4C accumulates in nucleus. Through interaction with β-catenin, KDM4C binds to and demethylates TCF4-associate Histone H3K9 which leads to HP1 removal and transcription activation. KDM4C-dependent H3K9 demethylation is essential for Wnt-induced gene expression and tumorigenesis. Importantly, KDM4C levels directly correlate with Wnt signaling activation in human glioblastomas. These findings demonstrate a pivotal epigenetic regulation mechanism for Wnt/β-catenin signaling activation in tumorigenesis.
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Project description:Previous studies have shown that the main function of VASP is to regulate the cytoskeleton and play an important role in promoting tumor cell metastasis. In this study, we first reveal that VASP is located in the nucleus of breast cancer cells and elucidate a Wnt/β-catenin/VASP positive feedback loop. We identify that VASP is a target gene of Wnt/β-catenin signaling pathway, and activation of Wnt/β-catenin signaling pathway can significantly upregulate VASP protein expression, while upregulated VASP protein can in turn promote translocation of β-catenin and DVL3 proteins into the nucleus. In the nucleus, VASP, DVL3, β-catenin and TCF4 can form VASP/DVL3/β-catenin/TCF4 protein complex, activating Wnt/β-catenin signaling pathway, and promoting the expression of target genes VASP, c-myc and cyclin D1. Thus, our study reveals that there is a Wnt/β-catenin/VASP malignant positive feedback loop in breast cancer, which promotes the proliferation and migration of breast cancer cells, and breaking this positive feedback loop may provide new strategy for breast cancer treatment.
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Project description:Previous studies have shown that the main function of VASP is to regulate the cytoskeleton and play an important role in promoting tumor cell metastasis. In this study, we first reveal that VASP is located in the nucleus of breast cancer cells and elucidate a Wnt/β-catenin/VASP positive feedback loop. We identify that VASP is a target gene of Wnt/β-catenin signaling pathway, and activation of Wnt/β-catenin signaling pathway can significantly upregulate VASP protein expression, while upregulated VASP protein can in turn promote translocation of β-catenin and DVL3 proteins into the nucleus. In the nucleus, VASP, DVL3, β-catenin and TCF4 can form VASP/DVL3/β-catenin/TCF4 protein complex, activating Wnt/β-catenin signaling pathway, and promoting the expression of target genes VASP, c-myc and cyclin D1. Thus, our study reveals that there is a Wnt/β-catenin/VASP malignant positive feedback loop in breast cancer, which promotes the proliferation and migration of breast cancer cells, and breaking this positive feedback loop may provide new strategy for breast cancer treatment.
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Project description:β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation.
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Project description:Wnt/β-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating β-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment β-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy.
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Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer. mRNAs from normal (WT, Notch-activated and Notch-inactivated) and tumor (WT, Notch-activated and Notch-inactivated) tissues were profiled.
2011-04-19 | E-GEOD-21392 | biostudies-arrayexpress
Project description:To analyze whether Wnt inhibitors LF3 and ICG-001 have similar influence on the gene expression of mouse salivary gland cancer stem cells Wnt/β-catenin signaling is a system that is essential for embryogenesis and tissue homeostasis which has been highly conserved through evolution. A deregulation of Wnt/β-catenin signals can initiate and promote human cancers, specifically of the colon, head and neck. As such, Wnt/β-catenin signaling represents an attractive target for cancer therapy. So far, however, no rationally developed compound targeting Wnt signaling has found clinical use. The interaction between β-catenin and TCF4 is necessary in the transduction of the signal; here we performed a High-Throughput-Screening (HTS) using AlphaScreen and ELISA techniques to identify small molecules that specifically disrupt this interaction. We identified compound LF3, a 4-thioureido-benzenesulfonamide derivative, as a robust inhibitor of β-catenin/TCF4 interactions and thus a good starting point for drug discovery, as suggested by Lipinski's “rule of five.” LF3 inhibited Wnt/β-catenin signaling in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. Medicinal chemistry identified an essential core structure and residues that could not be modified in LF3. Compound LF3 inhibited a number of features of cancer cells related to Wnt signaling, including high cell motility in Boyden chamber assays, hyperproliferation through induction of cell cycle arrest at the G1 phase, and the overexpression of key Wnt target genes. LF3 does not cause apoptosis or cell death or interfere with cadherin-mediated cell-cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentration-dependent manners, as demonstrated by examination of sphere formation of colon and head and neck cancer stem cells in serum-free, non-attached conditions. LF3 also reduced tumor growth and induced differentiation in colon tumors in mouse xenografts. LF3 is thus a specific inhibitor of canonical Wnt signaling with a significant potential for further development for preclinical and clinical studies in cancer treatment.
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