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DUSP4 deficiency due to promoter hypermethylation drives oncogenic JNK signaling and tumor cell survival in diffuse large B-cell lymphoma

ABSTRACT: DUSP4 deficiency due to promoter hypermethylation drives oncogenic JNK signaling and tumor cell survival in diffuse large B-cell lymphoma

PROVIDER: PRJEB7260 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR599183.fastq.gz	Fastqsanger.gz
	ERR599184.fastq.gz	Fastqsanger.gz
	ERR599185.fastq.gz	Fastqsanger.gz
	ERR599186.fastq.gz	Fastqsanger.gz
	ERR599187.fastq.gz	Fastqsanger.gz

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Similar Datasets

DUSP4 deficiency due to promoter hypermethylation drives oncogenic JNK signaling and tumor cell survival in diffuse large B-cell lymphoma

Project description:The epigenetic dysregulation of tumor suppressor genes is a major driver of human carcinogenesis. We have combined genome-wide methylation analyses with functional screening to identify novel candidate tumor suppressor genes in diffuse large B-cell lymphoma (DLBCL). We find that the dual-specificity phosphatase DUSP4 is aberrantly silenced in nodal and extranodal DLBCL due to promoter hypermethylation; ectopic expression of wild type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. JNK inhibition prevents DLBCL survival in vitro and in vivo, and synergizes strongly with inhibitors of chronic active B-cell receptor signaling. Our results provide a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, alone or in synthetic lethal combinations. A methylation profiling data set related to this experiment was also deposited at ArrayExpress under accession number E-MTAB-2926: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2926/

2015-03-25 | E-MTAB-2925 | biostudies-arrayexpress

DUSP4 deficiency due to promoter hypermethylation drives oncogenic JNK signaling and tumor cell survival in diffuse large B-cell lymphoma (methylation profiling data)

Project description:The epigenetic dysregulation of tumor suppressor genes is a major driver of human carcinogenesis. We have combined genome-wide methylation analyses with functional screening to identify novel candidate tumor suppressor genes in diffuse large B-cell lymphoma (DLBCL). We find that the dual-specificity phosphatase DUSP4 is aberrantly silenced in nodal and extranodal DLBCL due to promoter hypermethylation; ectopic expression of wild type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. JNK inhibition prevents DLBCL survival in vitro and in vivo, and synergizes strongly with inhibitors of chronic active B-cell receptor signaling. Our results provide a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, alone or in synthetic lethal combinations. RNA-seq expression profiling data set related to this experiment was also deposited at ArrayExpress under accession number E-MTAB-2925: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2925/

2015-03-25 | E-MTAB-2926 | biostudies-arrayexpress

DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma.

Project description:The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton's tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling.

| S-EPMC4419353 | biostudies-literature

DUSP4 silencing

Project description:DUSP4 silencing

| PRJNA897936 | ENA

DUSP4 silencing

Project description:siRNA mediated DUSP4 silencing in a cell line derived from a) AKT/NRAS double injected hepatocellular carcinoma in a mouse by hydrodynamic injection => AKT/NRAS and b) these cell lines with Cre knockout for AKT => AKT/NRAS Cre

2022-11-06 | GSE217233 | GEO

Identification of genes regulated by DUSP4

Project description:In this study, we compared expression profiles between colorectal cancer cell line HCT116 with and without DUSP4 knockdown.

2021-03-23 | GSE145511 | GEO

Homo sapiens

Project description:DUSP4 deficiency due to promoter hypermethylation drives oncogenic JNK signaling and tumor cell survival in diffuse large B-cell lymphoma

| PRJNA260880 | ENA

Identification of genes regulated by DUSP4

Project description:Identification of genes regulated by DUSP4

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A chromatin-modifying function of JNK during stem cell differentiation

Project description:Signaling mediates cellular responses to extracellular stimuli. The c-Jun NH2-terminal kinase (JNK) pathway exemplifies one sub-group of Mitogen-activated protein (MAP) kinases, which besides established functions in stress response, also contributes to developmental processes by an unknown mechanism 1-4. Here we show by genome-wide location analysis that JNK binds directly to a large set of active promoters during differentiation of stem cells to neurons. Bound promoters are not enriched for the canonical AP?1 target sites yet for binding motifs for the transcription factor NF?Y. NF-Y indeed occupies these predicted sites genome-wide in vivo and overexpression of a dominant-negative form of NF?YA reduces JNK presence on chromatin. Histone H3 is a substrate for JNK kinase activity in vitro and JNK bound promoters are preferentially enriched for Histone H3 phosphorylated at Serine 10. Inhibition of JNK signaling in postmitotic neurons reduces this chromatin phosphorylation as well as expression of target genes. Together this establishes MAP kinase binding and function on chromatin at a novel class of target genes during stem cell differentiation. Our Dataset comprises 5 ChIP-seq samples using chromatin from ES, NP and TN cells which was immunoprecipitated, using antibodies against H3K27me3, H3K4me2, RNA Pol II, JNK1/3 and NF-YA. From the same cells we generated biological replicates of RNA-seq data.

2011-12-18 | E-GEOD-25532 | biostudies-arrayexpress

Gene expression profiling of MDA231, BT549, and SUM159PT cells after selumetinib treatment or DUSP4 siRNA knockdown

Project description:MDA231, BT549, and SUM159PT basal-like breast cancer cell lines were transfected with non-targeting siRNA (siCONTROL), siRNA targeting DUSP4 (siDUSP4), or siCONTROL + 4 or 24 hr of 1uM selumetinib. Cells were harvested at 96 hr post-siRNA transfection. Data were Log2 RMA normalized. We sought to identify changes in gene expression after MEK inhibition, or after loss of DUSP4 function in breast cancer cell lines.

2013-09-03 | E-GEOD-41816 | biostudies-arrayexpress

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