Ontology highlight
ABSTRACT:
PROVIDER: PRJNA611802 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11282455_1.fastq.gz | Fastqsanger.gz | |||
| SRR11282455_2.fastq.gz | Fastqsanger.gz | |||
| SRR11282456_1.fastq.gz | Fastqsanger.gz | |||
| SRR11282456_2.fastq.gz | Fastqsanger.gz | |||
| SRR11282457_1.fastq.gz | Fastqsanger.gz |
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Project description:Lung cancer is a leading cause of cancer-related mortality worldwide and poor prognosis remains a major problem encountered in its treatment. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has been recently implicated in the tumorigenesis and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of YTHDF2 in the regulation of lung adenocarcinoma (LUAD) progression remain elusive. Here we report that YTHDF2 expression was significantly increased in lung adenocarcinoma than in adjacent normal tissues. YTHDF2 knockdown drastically inhibited cell proliferation, colony formation, and migration in vitro, and the opposite proved true when YTHDF2 was overexpressed. In addition, YTHDF2 attenuation significantly inhibited tumorigenesis in a murine tumor xenograft model. Through the integrative analysis of RNA-seq, m6A-seq, CLIP-seq, and RIP-seq datasets, we identified a set of potential direct targets of YTHDF2 in lung adenocarcinoma. We further confirmed AXIN1, which encodes a negative regulator of the Wnt/β-catenin signaling, as a direct target of YTHDF2. YTHDF2 promotes AXIN1 RNA decay and subsequently activates the Wnt/β-catenin signaling. Knockout of AXIN1 can sufficiently rescue the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. Collectively, our results uncovered YTHDF2-mediated regulation of the AXIN1/Wnt/β-catenin signaling that contributes to LUAD tumorigenesis, and thus provided insight into the mechanisms underlying lung adenocarcinoma progression.
2021-05-19 | GSE161090 | GEO
Project description:Aberrant activation of Wnt/β-catenin signaling is observed in numerous cancers. In hepatocellular carcinoma activating mutations in CTNNB1 (20-25%) or loss of function mutations in AXIN1 (10%), AXIN2 (2%) and APC (1-2%) are observed. All these mutations lead to aberrant stabilization of β-catenin, which constitutively activates downstream Wnt/β-catenin target genes and triggers a genetic program resulting in tumor formation. However, in relation to AXIN1 mutations some reports have challenged whether these indeed result in tumor growth by enhancing β-catenin signaling (e.g. PMID: 16964294, 29525529). Several alternative pathways have also been linked to AXIN1 (ENSG00000103126), such as TGFβ, SAPK/JNK, p53, YAP/TAZ and c-myc. To identify which one of these or other unknown signaling routes are linked to AXIN1, using CRISPR-Cas9 genome editing, we have successfully repaired the homozygous p.R712* AXIN1 mutation present in the SNU449 hepatocellular carcinoma cell line. Next, using RNA sequencing the RNA expression patterns of 3 independent repaired clones were compared with 3 clones retaining the AXIN1 mutation. Surprisingly, only 5 genes were significantly altered in the repaired clones, among which AXIN2, a well-established β-catenin target gene. Thus, this analysis leads to the surprising observation that a commonly observed mutation in a hepatocellular tumor suppressor gene, is associated with minimal alterations in gene expression, at least in the SNU449 cell line.
2019-01-01 | GSE119001 | GEO
Project description:Resistance to Ras pathway inhibition is a major challenge in the treatment of colorectal cancer (CRC), but the underlying mechanisms are incompletely understood. Here we performed large-scale small molecule screens in CRC and identified inhibitors of MEK1/2 as potent activators of Wnt/beta-catenin signalling. Targeting MEK increased Wnt activity in different CRC cell lines and in the murine intestine in vivo. The MEK-induced Wnt response was strongly enhanced by truncating mutations in APC and proteomic experiments identified that AXIN1 levels are depleted upon MEK inhibition. We generated patient-derived colon cancer organoids and showed that a clinically approved MEK inhibitor leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stem cells and cancer relapse. This reprogramming was reverted by co-treatment with Wnt inhibitors. Our study demonstrates that MEK inhibition affects cellular plasticity and induces an intestinal stem cell program which constitutes a novel mechanism of drug resistance.
2018-05-08 | GSE114060 | GEO
Project description:Resistance to Ras pathway inhibition is a major challenge in the treatment of colorectal cancer (CRC), but the underlying mechanisms are incompletely understood. Here we performed large-scale small molecule screens in CRC and identified inhibitors of MEK1/2 as potent activators of Wnt/beta-catenin signalling. Targeting MEK increased Wnt activity in different CRC cell lines and in the murine intestine in vivo. The MEK-induced Wnt response was strongly enhanced by truncating mutations in APC and proteomic experiments identified that AXIN1 levels are depleted upon MEK inhibition. We generated patient-derived colon cancer organoids and showed that a clinically approved MEK inhibitor leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stem cells and cancer relapse. This reprogramming was reverted by co-treatment with Wnt inhibitors. Our study demonstrates that MEK inhibition affects cellular plasticity and induces an intestinal stem cell program which constitutes a novel mechanism of drug resistance.
2018-05-08 | GSE114059 | GEO
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.
2019-12-01 | GSE92483 | GEO
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.
2024-01-06 | MSV000093784 | MassIVE
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.
2020-11-17 | GSE107094 | GEO
Project description:The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown. We found that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/β-catenin signaling in HB patients. GREB1 was localized to the nucleus where it bound Smad2/3 in a competitive manner with p300 and inhibited TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of β-catenin, YAP, and c-Met induced HB-like mouse liver tumor (BYM mice), with an increase in GREB1 expression and HB markers. Depletion of GREB1 strongly suppressed marker gene expression and HB-like liver tumorigenesis, and instead enhanced TGFβ signaling in BYM mice. Furthermore, antisense oligonucleotides for GREB1 suppressed the formation of HepG2 cell-induced tumors and HB-like tumors in vivo. We propose that GREB1 is a novel target molecule of Wnt/β-catenin signaling and required for HB progression.
2019-07-18 | GSE133976 | GEO
Project description:Peroxisomes are membrane-bound organelles that help cells specialize their metabolism. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. Thus, we performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that transcriptional inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), dramatically reduced the import of proteins into peroxisomes. The observed RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerase tankyrase, which binds the peroxisomal membrane protein PEX14. We propose a model in which RNF146 and tankyrase regulate peroxisome import efficiency by tuning PARsylation of proteins at the peroxisome membrane. Interestingly, we found that perturbations to peroxisomes altered tankyrase’s selection of substrates, including the beta-catenin destruction complex component AXIN1. The loss of peroxisomes caused tankyrase and RNF146-dependent degradation of AXIN1 and a concomitant increase of beta-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation, but also a novel role in bridging peroxisome function with Wnt/beta-catenin signaling during development.
2024-06-01 | GSE266855 | GEO
Project description:Peroxisomes are membrane-bound organelles that help cells specialize their metabolism. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. Thus, we performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that transcriptional inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), dramatically reduced the import of proteins into peroxisomes. The observed RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerase tankyrase, which binds the peroxisomal membrane protein PEX14. We propose a model in which RNF146 and tankyrase regulate peroxisome import efficiency by tuning PARsylation of proteins at the peroxisome membrane. Interestingly, we found that perturbations to peroxisomes altered tankyrase’s selection of substrates, including the beta-catenin destruction complex component AXIN1. The loss of peroxisomes caused tankyrase and RNF146-dependent degradation of AXIN1 and a concomitant increase of beta-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation, but also a novel role in bridging peroxisome function with Wnt/beta-catenin signaling during development.
2024-06-01 | GSE266892 | GEO