A super-enhancer regulated RNA-binding protein cascade drives pancreatic cancer
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE234078 | GEO | 2023/06/07
REPOSITORIES: GEO
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using an unbiased analysis of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in vivo. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.
2023-06-15 | PXD030423 | Pride
Project description: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.
2021-06-25 | GSE130242 | GEO
Project description:Super Enhancers are a class of DNA Cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis.Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, current research is far from sufficient to reveal the complex mechanisms behind epigenetic modifications.The aim of this study is to explore the function and mechanism of a new Super Enhancer in Pancreatic ductal adenocarcinoma (PDAC) tumors. By using epigenetic modification and chromatin interaction information, we found a new Super Enhancer enriched with abnormal active histone modifications in PDAC tumors and cells, called DKK1-super-enhancer (DKK1-SE).DKK1-SE was grouped according to the activity modification information, and the e1 component was identified as the main active unit by dual luciferase reporter gene system and dCas9-KRAB system.DNA motif analysis and core site deletion assay revealed that the e1 component possessed AP1 transcription factor family binding sites.Mechanically, AP1 activates DKK1 transcriptional activity by recruiting JUND and FOSL2 to induce enhancer chromatin remodeling.CRISPR/ Cas9-mediated deletion of DKK1-SE resulted in significant downregulation of its target gene DKK1.Analysis of TCGA data of PDAC tumors combined with immunohistochemical results of PDAC patients demonstrated that DKK1 was closely related to malignant clinical features of PDAC.Bioinformatics analysis of RNA-seq data showed that DKK1 was mainly related to tumor-related biological functions such as extracellular matrix, cell adhesion, angiogenesis, and cell proliferation.Cell malignant phenotype assay showed that deletion or interference of DKK1-SE significantly inhibited the proliferation, colony formation, migration and invasion of PANC-1, and these phenomena were partially alleviated after restoring DKK1 expression in DKK1-SE deficient cells.Experiments of Subcutaneous transplantation tumor in nude mice and Orthotopic transplantation tumor model showed that DKK1-SE deletion not only inhibited tumor proliferation, but also reduced the complexity of tumor microenvironment, resulting in less angiogenesis of tumor tissues and reduced fibrosis degree.In conclusion, DKK1-SE drives the expression of DKK1 by recruiting AP1 family transcription factors, which plays a carcinogenic role in PDAC tumors and enhances the complexity of the tumor microenvironment.
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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.
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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.
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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.
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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.
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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.
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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.
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