Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Protein Arginine Methyltransferase 5 (PRMT5) has prognostic relevance and is a druggable target in Multiple Myeloma

ABSTRACT: Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression free survival and overall survival. Either genetic knockdown or pharmacological inhibition of PRMT5 with the inhibitor EPZ015666 significantly inhibited growth of both cell lines and patient MM cells. Furthermore, PRMT5 inhibition abrogated NF-kB signaling. Interestingly, mass spectrometry identified a tripartite motif-containing protein 21 TRIM-21 as a new PRMT5-partner, and we delineated a TRIM21-dependent mechanism of NF-kB inhibition. Importantly, oral administration of EPZ015666 significantly decreased MM growth in a humanized murine model of MM. These data both demonstrate the oncogenic role and prognostic relevance of PRMT5 in MM pathogenesis, and provide the rationale for novel therapies targeting PRMT5 to improve patient outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103966 | GEO | 2017/09/19

SECONDARY ACCESSION(S): PRJNA407799

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Genome-wide CRISPR/Cas9 loss-of-function screen for prostate cancer cell line

Project description:Prostate cancer (PCa) is the most frequently diagnosed malignancy in men worldwide. Epigenetic regulation has been recognized as a main mechanism of cancer evolution. PRMT5 is the major type II protein arginine methyltransferase catalyzing the symmetric dimethylation of arginine in mammalian. PRMT5 is found upregulated in PCa. However, its exact functional contribution to prostate tumorigenesis is unknown. PRMT5 inhibition via pharmacological inhibition (EPZ015666) reduces stemness with paralleled differentiation and arrests cell cycle progression but without causing appreciable apoptosis.To understand the mechanisms of cell tolerance to PRMT5 inhibition and to identify potential pathways that function synergistically with EPZ015666, we performed a genome-wide CRISPR/Cas9 loss-of-function screen in the presence of EPZ015666. Our data unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target castration-resistant PCa when used in synergy with EPZ015666 at low doses. Genome-wide CRISPR/Cas9 loss-of-function screen in the presence of EPZ015666 in DU145

2024-09-03 | GSE222018 | GEO

NF-kB activation confers a prolonged event-free-survival in newly diagnosed myeloma patients harboring t(4;14) treated with bortezomib.

Project description:NF-kB pathway activation is the hallmark of hematological malignancies. In multiple myeloma (MM), a large variety of genomic alterations leading to either inactivation of repressor such as TRAF3, CYLD or cIAP1/2 or amplification of activators such as CD40 or NIK collectively contribute to frequently deregulate NF-kB signaling. In order to evaluate the prognostic impact of NF-kB mutations in MM, we performed a comprehensive analysis of a panel of newly diagnosed patients with cIAP1/2 biallelic deletion. We found that all patients have dysregulated NF-kB pathway and the majority of them presented t(4;14). Then we analyzed clinical outcome of 37 MM at presentation with t(4;14) and treated with bortezomib according to their NF-kB status. We showed that increase of NF-kB activity confers prolonged event-free survival. Altogether, our data suggest that NF-kB activation resulting from NF-kB mutations (ie cIAP1/2 deletion) or other mechanisms improves outcome of t(4;14)-positive MM treated with bortezomib.

2015-09-15 | GSE31272 | GEO

ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment (RNA-Seq)

Project description:Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here we identify and validate that TNF receptor associated factor protein family TRAF2 KD/KO in MM cells mediates IMiDs resistance via activation of non-canonical NF-kB and MEK-ERK signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-a induces proteasomal degradation of TRAF2, non-canonical NF-kB, and downstream ERK signaling in MM cells, whereas IL-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiDs sensitivity of TRAF2 KO cells both in vitro and in vivo using an inducible TRAF2 KD MM xenograft model. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiDs resistance in the BM microenvironment and improve patient outcome in MM.

2021-06-15 | GSE171340 | GEO

ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment (CRISPR Screen)

2021-06-15 | GSE171339 | GEO

PRMT5 regulated transcriptome in prostate cancer cells

Project description:Compared to intensely studied DNA methylation, protein methylation is less studied. PRMT5 is the major type II protein arginine methyltransferase catalyzing the symmetric dimethylation of arginine. Recent reports have indicated that PRMT5 is overexpressed in multiple cancer types, including prostate. However, the exact contribution of PRMT5 to prostate tumorigenesis is unknown. To explore PRMT5 in prostate cancer (PCa) therapeutically, we utilized a recently developed selective small molecule PRMT5 inhibitor (PRMT5i, EPZ015666) that has shown in vivo potency in MCL models. To understand the molecular mechanisms of action of PRMT5i in PCa, we performed deep RNA-seq analysis in PC3 and LNCaP cells treated with or without PRMT5i at 4 μM for 4 days in vitro.

2023-12-25 | GSE114151 | GEO

Transcriptional modulation by PRMT5 inhibition with EPZ015666 (GSK3235025)

Project description:Aberrant protein arginine methylation has been observed in multiple cancer types, making it an attractive drug target. Proteins can undergo asymmetric arginine methylation by type I protein arginine methyltransferases (PRMTs), predominately by PRMT1 and to a lesser extent PRMT4, or symmetric arginine methylation by type II PRMTs, predominately PRMT5. Here, we performed targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across cancer cell lines. We found that inhibition of both type I and type II PRMTs suppressed levels of total and phosphorylated ATR protein in cancer cell lines, and down-regulated expression of the ATR gene. Loss of ATR from PRMT inhibition resulted in defective DNA replication stress response activation in following exogenous replication stress. Since PARP inhibitors are known to induce replication stress, we next combined PRMT inhibition with PARP inhibition and found inhibition of PRMT1 or PRMT5 greatly exacerbated PARP inhibitor induced DNA damage. Based on this observation, we assessed the combination of PARP and PRMT inhibition in a panel of cell lines. While inhibition of both type I and type II PRMTs were synergistic with PARP inhibition in both cells with intact and deficient homologous recombination, type I PRMT inhibition resulted in higher toxicity in non-malignant cells. Therefore, we validated the synergy of combined PARP/PRMT5 inhibition in primary patient-derived organoids. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves overall survival in both BRCA-mutant and wild-type patient-derived xenograft models without any detectable hematological toxicities typically associated with PARPi combination therapies. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to improve tumor sensitivity to PARP inhibition. .

2023-10-26 | GSE246325 | GEO

Transcriptional modulation by PRMT5 inhibition with EPZ015666 (GSK3235025)

Project description:Transcriptional modulation by PRMT5 inhibition with EPZ015666 (GSK3235025)

| PRJNA1032548 | ENA

Disruption of splicing, proliferation and stemness via PRMT5 inhibition as a therapeutic strategy for GBM

Project description:Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein Arginine Methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition caused widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.

2020-11-03 | PXD021635 | Pride

Expression data of lentivirus sponge Protein Arginine Methyltransferase 5 downregulated NCI-H929 cell line compared with control lentivirus sponge

Project description:Multiple myeloma is characterized by frequent chromosomal alterations. Protein Arginine Methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. We sought to functionally validate the role of PRMT5 and delineate their downstream target genes in MM. Using “sponge” lentiviral vectors to knock down PRMT5 in vitro and in vivo, we have documented enhanced apoptosis and descend proliferation of MM cells compared with control lentivirus sponge . Expression profiling analysis of PRMT5-deficient cells identified a large number of downstream target genes, which provides a valuable tool to investigate their function in MM pathogenesis and their potential use as therapeutic targets.

2020-12-06 | GSE162715 | GEO

RNA-seq of human multiple myeloma cell lines JJN3, OPM2 and XG7 with PRMT5 inhibitor EPZ015938 versus untreated controls.

Project description:Evaluation of anti-myeloma effects of inhibition of PRMT5, involved in arginine methylation. Three human multiple myeloma cell lines were treated with the PRMT5 inhibitor EPZ015938. Transcriptional profiles were compared to untreated controls.

2022-03-11 | E-MTAB-11489 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data