Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PRMT1-dependent regulation of RNA metabolism and DNA damage response is a critical dependency in pancreatic ductal adenocarcinoma

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, which represents a critical area of unmet need for novel therapeutic options. Here we deployed an RNAi-based in vivo functional genomics platform to identify epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this effort, we identified protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validated the role of PRMT1 in maintaining PDAC growth and informed the mechanism-of-action through proteomic and transcriptomic analyses. Mechanistically, we showed that inhibition of asymmetric arginine methylation globally impaired RNA metabolism, including RNA splicing, alternative polyadenylation, and transcription termination, causing a profound down-regulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, these data support PRMT1 as a compelling target in PDAC and inform a mechanism-based translational strategy for future therapeutic development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130242 | GEO | 2021/06/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

PRMT1 Promotes Epigenetic Reprogramming Associated with Acquired Chemoresistance in Pancreatic Cancer

Project description:Pancreatic Ductal Adenocarcinoma (PDAC) is associated with extremely poor prognosis due to late diagnosis and therapeutic resistance. Here we show that PDAC cells undergo progressive reprogramming of the global epigenetic landscape during the process of acquiring chemoresistance. Through an epigenetic inhibitor screen, we identified Protein Arginine methyltransferase 1 (PRMT1) as a central driver of chemoresistance in PDAC. Genetic or pharmacological inhibition of PRMT1 impaired adaptive epigenetic reprogramming, sensitized PDAC cells to Gemcitabine and other commonly used chemo drugs, and delayed the development of acquired resistance both in vitro and in vivo. Mechanistically, we find that PRMT1, through its enzymatic activity, limits the accumulation of small bZIP transcription factor MAFF in the nucleus, and the assembly of chromatin-bound MAFF/BACH1 hetero-oligomeric complexes following Gemcitabine treatment. Genetic silencing of MAFF heightened the resistance of PDAC cells to Gemcitabine, and to combination of Gemcitabine and PRMT1 inhibitors. Cut&Tag chromatin profiling of H3K27Ac, MAFF and BACH1 suggests a pivotal role for MAFF/BACH1 in orchestrating global epigenetic reprogramming during the course of acquiring Gemcitabine resistance. Supporting the clinical relevance of our findings, predicted PRMT1 and MAFF/BACH1 genes signatures based on our Cut&Tag analysis were able to distinguish Gemcitabine-resistant from Gemcitabine-sensitive PDAC patient-derived xenografts according to expression changes induced by Gemcitabine. Together, our study reveals a novel epigenetic regulatory axis involving PRMT1 and MAFF/BACH1 that modulates Gemcitabine response, which could be potentially exploited for improving therapeutic response in advanced PDAC.

2024-04-29 | GSE227129 | GEO

Targeting PRMT1-mediated SRSF1 Methylation to Suppress Exon Inclusion within Oncogenic Transcripts and Breast Tumorigenesis

Project description:PRMT1 is highly expressed in breast tumors, and has been suggested to play a vital role in breast tumorigenesis, but the underlying molecular mechanisms remain to be fully characterized. Here, we reveal that PRMT1 exhibits a wide-spreading role in RNA alternative splicing based on transcriptome analysis, with a preference for exon inclusion in a large cohort of oncogenic genes. Profiling PRMT1 methylome reveals that the arginine/serine-rich splicing factor SRSF1 is heavily arginine-methylated by PRMT1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and PRMT1-induced exon inclusion. In breast tumors, the overexpression of PRMT1 is associated with high levels of SRSF1 arginine methylation and aberrant exon inclusion in those oncogenic genes. Accordingly, PRMT1-mediated SRSF1 methylation and exon inclusion events are found to be critical for the malignant behaviors of breast cancer cells. Furthermore, we identified and characterized a selective PRMT1 inhibitor iPRMT1, which is potent in inhibiting PRMT1-mediated SRSF1 methylation and exon inclusion events, and breast cancer cell growth both in vitro and in vivo. Combination treatment with iPRMT1 and inhibitor targeting SRSF1 phosphorylation, SPHINX31 or SRPIN340, exhibits synergistic effects on suppressing breast cancer cell growth, strengthening the cross-talk between arginine methylation and phosphorylation in SRSF1. In conclusion, our data uncover a key mechanism underlying PRMT1-mediated gene alternative splicing, demonstrating targeting PRMT1 has great potential to treat breast cancer in clinic.

2023-10-02 | GSE212049 | GEO

PRMT1 promotes pancreatic cancer development and resistance to chemotherapy

Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of, and potential as a therapeutic target for, PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that the PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.

2024-03-09 | GSE223133 | GEO

PRMT1 promotes pancreatic cancer development and resistance to chemotherapy

2024-03-09 | GSE223154 | GEO

PRMT1 promotes pancreatic cancer development and resistance to chemotherapy

2024-03-09 | GSE223152 | GEO

PRMT1 promotes pancreatic cancer development and resistance to chemotherapy

2024-03-09 | GSE223146 | GEO

Transcription profiling of human HeLa cells follwing siRNA mediated knock down of the arginine methyltransferases CARM1 and/or PRMT1

Project description:siRNA mediated knockdown of the arginine methyltransferases CARM1 and/or PRMT1 in HeLa cells

2007-08-30 | E-MEXP-1173 | biostudies-arrayexpress

The arginine methyltransferase PRMT1 establishes transcriptomic homeostasis essential for spermatogonial differentiation and male fertility

Project description:Protein arginine methyltransferase 1 (Prmt1) is known as the major Type-I protein arginine methyltransferase that deposits asymmetrical dimethylarginine (ADMA) in both histone and non-histone substrates. Nonetheless, how Prmt1 and its downstream signalling through substrate methylation function in the male germline development remains poorly understood. In this study, we discovered that Prmt1 is predominantly present in the spermatogonial population during mouse spermatogenesis. Using three Cre-mediated conditional Prmt1 knockout mouse lines, we observed that Prmt1 is essential for the maintenance of spermatogonial cells and Prmt1-deposited ADMA marks coordinate an inherent homeostasis among three types of substrate methylation. In conjunction with high-throughput Cut&Tag and modified mini-bulk Smart-seq2 analyses, we unveiled that Prmt1-mediated H4R3me2a mark enriched in the promoter region, together with other histone arginine methylations, drives a global transcriptomic landscape that maintains the regular gene expression and alternative splicing. Collectively, we provide the genetic evidence showing the essential role of Prmt1-deposited arginine methylation in the establishment of transcriptional homeostasis, and shed light on the methylarginine signalling pathway in orchestrating spermatogonial development in the mammalian germline.

2023-03-31 | GSE227857 | GEO

PRMT1-dependent Arginine methylation regulates replication stress response through DNA-protein kinase

Project description:PRMT1 is the major Arginine methyltransferase in mammalian cells and its over-expression in human cancer has been linked to poor response to cancer therapy. Here, combining mass spectrometry-based global methyl-proteomics with genome-wide mRNA expression profiling, we identify PRMT1 and its associated Arginine methylation as a regulatory hubs controlling cancer cell response to replicative stress agents. We show that DNA-PK binds to PRMT1 and regulates both its subcellular localization and activity, leading to PRMT1 recruitment to drug-stalled replication forks and channelling its methyl-transferase activity from its soluble targets towards Arginine 3 of histone H4. This DNA-PK-PRMT1 axis is required for the induction of the Senescence-Associated Secretory Phenotype, which sustains cell cycle arrest and protects cells from apoptosis. Our data show that Arginine-methylation regulates the adaptive response of cancer cell to replicative stress agents and might be targeted to sensitize cancer cells to genotoxic chemotherapeutics

2020-01-14 | GSE106609 | GEO

Prmt1-mediated translation regulation is a crucial vulnerability of cancer

Project description:Through an shRNA screen we have identified Prmt1 as a genetic vulnerability of p53/Rb-null murine osteosarcoma cells. Depletion of Prmt1 in p53-deficient cells impairs tumor initiation and maintenance in vitro and in vivo. Mechanistic studies reveal that translation-associated pathways are enriched for Prmt1 downstream targets, implicating a role of Prmt1 in translation control. In particular, we have shown that loss of Prmt1 leads to a the decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. We also observed that p53/Rb-null cells are sensitive to p53-induced translation stress. Analysis of the human tumor cell Achilles data set further reveals that Prmt1 and translation-associated pathways converge on the same functional networks. We propose that targeted therapy directed to inhibition of Prmt1 and its associated translation-related pathways represents a novel and promising therapeutic strategy for p53-deficient cancer cells that exhibit dependencies on translation stress response.

2018-01-06 | GSE93309 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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