Cancer-relevant alternative RNA splicing events driven by the PRMT5-E2F1 axis in high risk neuroblastoma
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PROVIDER: PRJNA1020851 | ENA |
REPOSITORIES: ENA
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Project description:Neuroblastoma (NB) is a devastating childhood cancer that remains clinically unmet. There is an urgency to develop new approaches to treat the disease. Protein arginine methyltransferase (PRMT5) is over-expressed in a wide variety of cancers and has been implicated with a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. Here, we have investigated the relevance of the interplay between PRMT5 and E2F1 in neuroblastoma and found that elevated expression occurs in poor prognosis high-risk disease. Cell lines derived from NB that recapitulate high PRMT5 and E2F1 expression exhibit increased levels of alternative RNA splicing compared to their low expression cell counterparts. Cancer-relevant exon-skipping events in apoptotic genes were apparent in high expressing NB cells which resulted in protein isoforms with decreased apoptotic activity. Pharmacological inhibition of PRMT5 or inactivation of E2F1 activity reduced exon skipping and reinstated normal apoptotic activity. Our findings show that a cancer relevant alternative splicing programme desensitises high risk NB to apoptosis. The critical role ascribed to PRMT5 and E2F1 in attaining the alterative RNA splicing programme equally identifies PRMT5 as a potential therapeutic target for neuroblastoma disease.
2024-09-14 | GSE243989 | GEO
Project description:We identified distinct sets of genes under the control of PRMT5 and E2F1. Some of the most highly regulated genes, such as cortactin/CTTN, influenced cell migration, invasion and adherence. We characterised the functional role of the cortactin/CTTN gene, which enabled PRMT5 through E2F1 to promote cellular migration and invasion, whilst decreasing cellular adherence. Most significantly, there was a striking coincidence between the expression of PRMT5 and E2F1 in certain human tumours, and elevated levels of PRMT5, E2F1 and cortactin/CTTN correlated with poor prognosis disease. Our results suggest a causal relationship between PRMT5, E2F1 and the migration and invasion of cancer cells, thereby highlighting an important pathway that contributes to the cancer biology of tumour cells.
2020-07-28 | GSE142430 | GEO
Project description:Patients suffering from chronic lymphocytic leukemia (CLL) display highly diverse clinical courses ranging from indolent cases to aggressive disease with genetic and epigenetic features resembling this diversity. Here, we developed a comprehensive approach combining a variety of molecular and clinical data to identify translocation events disrupting long-range chromatin interactions and causing cancer-relevant transcriptional deregulation. Thereby, we identified a B cell specific cis-regulatory element restricting the expression of genes in the associated locus, including PRMT5 and DAD1, two factors with oncogenic potential. Examining the role of PRMT5 in CLL identified transcriptional programs associated with pathways of stress tolerance and growth support, maintaining MYC-driven gene expression in vivo and in vitro. Conversely, inhibition of PRMT5 impairs factors involved in DNA-repair and sensitizes cells for apoptosis. Finally, we show that artificial deletion of the regulatory element from its endogenous context resulted in upregulation of corresponding genes, including PRMT5. Furthermore, such disruption renders PRMT5 transcription vulnerable to additional stimuli and subsequently also alters the expression of downstream PRMT5 targets.
2020-08-19 | E-MTAB-8219 | biostudies-arrayexpress
Project description:Patients suffering from chronic lymphocytic leukemia (CLL) display highly diverse clinical courses ranging from indolent cases to aggressive disease with genetic and epigenetic features resembling this diversity. Here, we developed a comprehensive approach combining a variety of molecular and clinical data to identify translocation events disrupting long-range chromatin interactions and causing cancer-relevant transcriptional deregulation. Thereby, we identified a B cell specific cis-regulatory element restricting the expression of genes in the associated locus, including PRMT5 and DAD1, two factors with oncogenic potential. Examining the role of PRMT5 in CLL identified transcriptional programs associated with pathways of stress tolerance and growth support, maintaining MYC-driven gene expression in vivo and in vitro. Conversely, inhibition of PRMT5 impairs factors involved in DNA-repair and sensitizes cells for apoptosis. Finally, we show that artificial deletion of the regulatory element from its endogenous context resulted in upregulation of corresponding genes, including PRMT5. Furthermore, such disruption renders PRMT5 transcription vulnerable to additional stimuli and subsequently also alters the expression of downstream PRMT5 targets.
2020-08-19 | E-MTAB-8203 | biostudies-arrayexpress
Project description:1. To identify potential effectors responsible for anti-tumorigenesis by targeting PLD1, we performed microarray in two Wnt-relevant colon cancer cells and analyzed transcriptional profile of genes that were differently expressed by inhibition and knockdown of PLD1 2. We also investigated potential downstream effectors of PLD1-E2F1 axis using microarray analysis in PLD1 and E2F1-depleted CRC cells.
2015-06-03 | GSE55724 | GEO
Project description:Transcriptome analysis following inhibition of PRMT5 using GSK3203591 in MYCN amplified neuroblastoma
| PRJEB72851 | ENA
Project description:Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells deleted of TRPM2 with CRISPR technology. Viability was significantly decreased in TRPM2 knockout after doxorubicin treatment. RNA sequence analysis and RT-qPCR revealed reduced RNAs encoding master transcription regulators FOXM1 and E2F1/2 and downstream cell cycle targets including Cyclin B1, CDK1, PLK1, and CKS1. CHIP analysis demonstrated decreased FOXM1 binding to their promoters. Western blotting confirmed decreased expression, and increased expression of CDK inhibitor p21, a CKS1 target. In cells with TRPM2 deletion, cell cycle progression to S and G2/M phases was reduced after treatment with doxorubicin. RNA sequencing also identified decreased DNA repair proteins in cells with TRPM2 deletion after doxorubicin treatment, and DNA damage was increased. Wild type TRPM2 but not Ca2+-impermeable mutant E960D, restored live cell number and reconstituted expression of E2F1, FOXM1, and cell cycle/DNA repair proteins. FOXM1 expression alone restored viability. TRPM2 is a potential therapeutic target to reduce tumor proliferation and increase doxorubicin sensitivity through modulation of FOXM1, E2F1, and cell cycle/DNA repair proteins.
2022-02-25 | GSE197243 | GEO
Project description:E2F activity impacts on an extensive gene network mediated in part by PRMT5-dependent arginine methylation which widens its functional role in gene expression control. We show here that the PRMT5-E2F1 axis has an additional and unexpected level of control through facilitating expression of the non-coding genome where long non-coding (lnc) genes are direct targets for PRMT5 and E2F1. The expression of some lncRNAs results in their translation into small proteins, which then give rise to peptides which populate the MHC class I antigen presentation machinery. Pharmacological inhibition of PRMT5 alters the expression of lncRNA genes and thereby the repertoire lncRNA-derived peptides presented as MHC bound peptides. Delayed tumor growth upon PRMT5 inhibition reflects an influx of lncRNA peptide-specific cytotoxic CD8 T cells. When presented to the immune system as a stand-alone therapeutic vaccine, lncRNA-derived MHC-bound peptides are immunogenic and drive a potent anti-tumor T cell response with a significant delay in tumor growth. Our results show that the PRMT5 through its control of the E2F pathway influences expression of the non-coding genome and derived peptides presented to the immune system, which can subsequently be harnessed to deliver an effective stand-alone cancer vaccine. These results have important implications for deploying pharmacological intervention to manipulate gene expression and antigen presentation to the immune system and deploying new types of cancer vaccine. They also indicate that cell cycle control through the E2F pathway is intimately connected with immune recognition.
2023-01-26 | GSE181401 | GEO
Project description:E2F1 has been shown to induce both proliferation and apoptosis. We now show that PI3K/Akt signaling regulates the balance of these events by specifically blocking expression of genes in the E2F1 apoptotic program but not the proliferative program. Keywords: PI3K dependent modulation of E2F1 gene expression measured by Affymetrix gene expression analysis
2007-11-02 | GSE9496 | GEO
Project description:E2F transcription factors are known regulators of the cell cycle, proliferation, apoptosis and differentiation. We reveal an essential role for E2F1 in liver through the regulation of glycolysis and lipogenesis. E2F1 deficiency leads to a decreased in glycolysis and de novo synthesis of fatty acids in hepatocytes. ChIP-Seq was performed to determine direct tagets of E2F1 in hepatocytes. We highlight that E2F1 directly binds the promoters of genes implicated in metabolic process and notably key lipogenic genes to control these pathways.
2015-12-01 | GSE74006 | GEO