PRMT1 Promotes Epigenetic Reprogramming Associated with Acquired Chemoresistance in Pancreatic Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA943270 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23814000.fastq.gz | Fastqsanger.gz | |||
| SRR23814000_1.fastq.gz | Fastqsanger.gz | |||
| SRR23814000_2.fastq.gz | Fastqsanger.gz | |||
| SRR23814001.fastq.gz | Fastqsanger.gz | |||
| SRR23814001_1.fastq.gz | Fastqsanger.gz |
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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
Project description:Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis due to therapeutic resistance. We show that PDAC cells undergo global epigenetic reprogramming to acquire chemoresistance, a process that is driven at least in part by protein arginine methyltransferase 1 (PRMT1). Genetic or pharmacological PRMT1 inhibition impairs adaptive epigenetic reprogramming and delays acquired resistance to gemcitabine and other common chemo drugs. Mechanistically, gemcitabine treatment induces translocation of PRMT1 into the nucleus, where its enzymatic activity limits the assembly of chromatin-bound MAFF/BACH1 transcriptional complexes. Cut&Tag chromatin profiling of H3K27Ac, MAFF, and BACH1 suggests a pivotal role for MAFF/BACH1 in global epigenetic response to gemcitabine, which is confirmed by genetically silencing MAFF. PRMT1 and MAFF/BACH1 signature genes identified by Cut&Tag analysis distinguish gemcitabine-resistant from gemcitabine-sensitive patient-derived xenografts of PDAC, supporting the PRMT1-MAFF/BACH1 epigenetic regulatory axis as a potential therapeutic avenue for improving the efficacy and durability of chemotherapies in patients of PDAC.
| S-EPMC11238875 | biostudies-literature
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 | GSE223154 | GEO
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 | GSE223152 | GEO
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 | GSE223146 | GEO
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
Project description:Transcriptional deregulation plays a major role in acute myeloid leukemia, identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence showing the functional involvement and therapeutic potentials of targeting PRMT1 with H4R3 methyltransferase activity in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C with H3K9 demethylase activity by chimeric transcription factors to mediate epigenetic reprogramming. Inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a novel and targetable epigenetic circuitry mediated by PRMT1 and KDM4C in acute leukemia.
2016-01-14 | E-MTAB-3322 | biostudies-arrayexpress
Project description:The protein arginine methyltransferase PRMT1 is overexpressed in various human cancers and linked to poor response to therapy. Although various inhibitors targeting its activity are under development, we still do not fully understand how PRMT1 is involved in the cellular processes underpinning tumorigenesis and chemoresistance. Mass spectrometry–based proteomics revealed PRMT1 as a regulator of global arginine methylation changes in response to replicative stress in cancer cells. We show that, upon cisplatin, DNA-dependent protein kinase binds to- and phosphorylates PRMT1, inducing its chromatin recruitment and redirecting its enzymatic activity from soluble protein targets towards the histone substrate Arg3 of histone H4 (H4R3). On chromatin, DNA-PK/PRMT1 axis induces the Senescence-Associated Secretory Phenotype through the deposition of H4R3me2a at the pro-inflammatory gene promoters and by sustaining p65 binding to chromatin. Finally, PRMT1 inhibition reduced the clonogenic outgrowth of ovarian cancer cells exposed to low doses of CDDP and sensitized them to apoptosis. While unravelling a novel role of PRMT1 in replication stress response, our findings suggest the opportunity of targeting PRMT1 to sensitize cancer cells to genotoxic chemotherapeutics.
2020-01-15 | PXD014799 | Pride
Project description:PRMT1 promotes pancreatic cancer development and resistance to chemotherapy
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Project description:PRMT1 promotes pancreatic cancer development and resistance to chemotherapy
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