Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mutant KRAS/BRAF Reprograms the Enhancer Landscape via GATA1 to Drive Chemoresistance

ABSTRACT: Despite advances in the detection and management of colorectal cancers, resistance to anti-cancer therapies remains a significant challenge. Activating mutations in KRAS and BRAF are frequently observed in colorectal cancers and have been associated with aggressive tumors and poor survival after chemotherapy. In the present study, we demonstrate that mutations in KRAS/BRAF alter the enhancer landscape of tumor cells, which leads to the resistance of the cornerstone colorectal cancer chemotherapeutic agent 5-fluorouracil (5-FU) through activation of transcription factor GATA1. Targeted inhibition of GATA1 reverses epigenetic changes in KRAS mutant cells and restores sensitivity to 5-FU. These results indicate a novel therapeutic opportunity for tailoring individualized therapy in human colorectal cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115400 | GEO | 2019/10/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

microRNA expression profile between KRAS/BRAF wild and BRAF mutant colorectal cancer

Project description:The genome-wide miRNA expression analysis was performed in clinical samples, comprising 15 BRAF-mutant and 15 non-KRAS/BRAF-mutant colorectal cancers by using a SurePrint G3 Human miRNA microarray. clinical samples, comprising 15 BRAF-mutant and 15 non-KRAS/BRAF-mutant colorectal cancers by using a SurePrint G3 Human miRNA microarray.

2016-04-01 | E-GEOD-66548 | biostudies-arrayexpress

microRNA expression profile between KRAS/BRAF wild and BRAF mutant colorectal cancer

2016-04-01 | GSE66548 | GEO

Mutant KRAS/BRAF Reprograms the Enhancer Landscape via GATA1 to Drive Chemoresistance

Project description:Mutant KRAS/BRAF Reprograms the Enhancer Landscape via GATA1 to Drive Chemoresistance

| PRJNA474834 | ENA

Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cellsLinking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells

Project description:Background: The Ras pathway genes KRAS, BRAF or ERBBs have somatic mutations in ~60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway, or whether they have acquired mutations in genes hitherto not known to belong to the pathway. Methods: To address the second possibility, and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted. Results: Of the 163 recurrently targeted genes in the two different genetic backgrounds, one third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, 9 genes also mutated in human colorectal cancers were identified. Among these, stable knock-down of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knock-down of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells. Conclusions: This work establishes a proof-of-concept that human cell based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.

2018-02-20 | PXD008382 | Pride

BRAF-induced tumorigenesis is IKKalpha dependent but NF?B independent

Project description:Tumor cells carrying KRAS mutations activate the NF-?B pathway by different mechanisms, which contribute to the acquisition of essential cancer properties. The BRAF kinase, a downstream mediator of KRAS, is also mutated in a subset of colorectal cancers (CRC), which predicts bad prognosis and therapy resistance. However, nothing is known on whether NF-?B participates of BRAF-mediated tumorigenesis. We here found that in CRC cells, mutant BRAF does not trigger canonical or alternative NF-?B signaling but induces p45-IKK? activation. Moreover, IKK? activity is required for BRAF-induced transformation and to support BRAF-dependent transcription in CRC cells. Activation of p45-IKK? downstream of BRAF requires the TAK1 kinase, and is associated to the endosomal compartment. Inhibition of endosomal V-ATPase abolished p45-IKK? phosphorylation, and induced apoptosis of BRAF mutated CRC cells. Pharmacologic inhibition of endosome acidification reduced the in vivo growth of tumors carrying mutant BRAF, and abrogated the metastatic capacity of a primary human CRC tumor with acquired resistance to standard chemotherapy in an orthotopic xenograft model. 18 samples were analyzed: HT29 controls (n=3); HT28 BRAF inhibited (n=3), WiDr controls (n=3); WiDr BRAF inhibited (n=3); WiDr transduced with control shRNA (n=3) and WiDr transduced with shRNA against IKKalpha (n=3)

2015-05-08 | E-GEOD-57979 | biostudies-arrayexpress

Identification of novel SNP candidates associated with chemo-responsiveness in colorectal cancers

Project description:Identificaiton of novel single-nucleotide polymorphism (SNP) candidates associated with chemo-responsiveness in colorectal cancers using microarray Response rates of 104 colorectal cancer patients to established regiments (FL, CAPE, FLOX, FLIRI) were evaluated by histoculture drug response assay. Affymetrix SNP 5.0 chips were used to determine genotypes of the same colorectal cancer patients. SNPs associated with chemosensitivity to standard regimens were identified by genome-wide association study. FL: 5-FU + Leucovorin; CA: Capecitabine, FLOX: 5-FU + Leucovorin + Oxaliplatin, FLIRI: 5-FU + Leucovorin + Irinotecan

2010-06-01 | GSE16718 | GEO

Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia

Project description:Nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We found that NSD1 knockdown altered erythroid clonogenic growth of human CD34+ hematopoietic cells. Ablation of Nsd1 in the hematopoietic system induced a transplantable erythroleukemia in mice. Despite abundant expression of the transcriptional master regulator GATA1, in vitro differentiation of Nsd1-/- erythroblasts was majorly impaired associated with reduced activation of GATA1-induced targets, while GATA1-repressed target genes were less affected. Retroviral expression of wildtype Nsd1, but not a catalytically-inactive Nsd1N1918Q SET-domain mutant induced terminal maturation of Nsd1-/- erythroblasts. Despite similar GATA1 levels, exogenous Nsd1 but not Nsd1N1918Q significantly increased GATA1 chromatin occupancy and target gene activation. Notably, Nsd1 expression reduced the association of GATA1 with the co-repressor SKI, and knockdown of SKI induced differentiation of Nsd1-/- erythroblasts. Collectively, we identified the NSD1 methyltransferase as a novel regulator of GATA1-controlled erythroid differentiation and leukemogenesis.

2020-04-08 | PXD017657 | Pride

BRAF-induced tumorigenesis is IKKalpha dependent but NFκB independent

Project description:Tumor cells carrying KRAS mutations activate the NF-κB pathway by different mechanisms, which contribute to the acquisition of essential cancer properties. The BRAF kinase, a downstream mediator of KRAS, is also mutated in a subset of colorectal cancers (CRC), which predicts bad prognosis and therapy resistance. However, nothing is known on whether NF-κB participates of BRAF-mediated tumorigenesis. We here found that in CRC cells, mutant BRAF does not trigger canonical or alternative NF-κB signaling but induces p45-IKKα activation. Moreover, IKKα activity is required for BRAF-induced transformation and to support BRAF-dependent transcription in CRC cells. Activation of p45-IKKα downstream of BRAF requires the TAK1 kinase, and is associated to the endosomal compartment. Inhibition of endosomal V-ATPase abolished p45-IKKα phosphorylation, and induced apoptosis of BRAF mutated CRC cells. Pharmacologic inhibition of endosome acidification reduced the in vivo growth of tumors carrying mutant BRAF, and abrogated the metastatic capacity of a primary human CRC tumor with acquired resistance to standard chemotherapy in an orthotopic xenograft model.

2015-05-08 | GSE57979 | GEO

Cell type-dependent differential activation of ERK by oncogenic KRAS in human colon cancer and mouse intestinal epithelium

Project description:Mutations activating the KRAS GTPase or the BRAF kinase are frequent in colorectal cancer and are thought to constitutively activate the terminal mitogen-activated protein kinase, ERK. Using mass cytometry, we found graded phosphorylation of ERK anti-correlated with cell differentiation in patient-derived colorectal cancer organoids, and unexpectedly this gradient was observed independently of KRAS mutational status. We therefore investigated differentiation-dependent signal transduction elicited by oncogenic KRAS or BRAF in transgenic mouse organoid models. Reporter, single cell transcriptome and mass cytometry analyses showed that transgenic expression of KRASG12V activated ERK in a cell type-specific pattern. Furthermore, expression of oncogenic KRAS induced the formation of RAS-ERK-responsive cells. In contrast, transgenic expression of BRAFV600E triggered high ERK activity and downstream gene expression in all intestinal cell types, followed by epithelial disorganisation. We analysed signal transduction to ERK using single cell-resolved network perturbation data in transgenic organoids. Network reconstruction followed by quantitative modelling revealed that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identify dual-specificity phosphatases as candidate modulators of MEK to ERK signal transduction. Our experiments highlight key differences between ERK activity elicited by the BRAF or KRAS oncogenes in colorectal cancer and find unexpected functional heterogeneity in a signalling pathway with fundamental relevance for cancer therapy.

2019-03-31 | GSE115242 | GEO

Homo sapiens

Project description:microRNA expression profile between KRAS/BRAF wild and BRAF mutant colorectal cancer

| PRJNA277301 | ENA