PRMT1 inhibition induces differentiation of colon cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA596539 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10737785.fastq.gz | Fastqsanger.gz | |||
| SRR10737786.fastq.gz | Fastqsanger.gz | |||
| SRR10737787.fastq.gz | Fastqsanger.gz | |||
| SRR10737788.fastq.gz | Fastqsanger.gz | |||
| SRR10737789.fastq.gz | Fastqsanger.gz |
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Project description:Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women, with over 1.8 million new cases in 20181. Differentiation therapy has been recently revisited as a prospective approach in cancer therapy2 by targeting the aberrant growth, differentiation and cell death programs of cancer cells. Standard of care chemotherapy may eradicate cancer cells, but the aggressive cells can survive and resistance gradually develops. In contrast, differentiation therapy aims not to eradicate cancer bulk, but rather directs cancer cells towards inhibited proliferation and restoration of the apoptotic program, while maintaining a limited toxicity. Current data suggests that differentiation therapy can be an effective anti-cancer treatment approach, however discovery of the new differentiation inducing molecules with a higher therapeutic index is essential. We performed HTS screen for compounds mediating differentiation of colon cancer cell using a novel dual multiplex assay3. Here we show that PRMT type 1 inhibitor MS023 is a potent inducer of colon cancer cell differentiation with a large therapeutic window. Our findings has a great importance for following investigation and development of effective differentiation based anti CRC therapy applicable in the clinic.
2021-09-09 | PXD016799 | Pride
Project description:Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women with over 1.8 million new cases in 20181. Differentiation therapy has been recently revisited as a prospective approach in cancer therapy2 by targeting the aberrant growth, and repairing differentiation and cell death programs of cancer cells. Standard of care chemotherapy may kill cancer cells, but the aggressive cells can survive and resistance gradually develops. In contrast, differentiation therapy aims not to eradicate cancer bulk, but rather directs cancer cells towards inhibited proliferation and restoration of the apoptotic program, while maintaining a limited toxicity. Current data suggests that differentiation therapy can be an effective anti-cancer treatment approach, however discovery of the new differentiation inducing molecules with a higher therapeutic index is essential. We performed High Throughput Screening (HTS) for discovery of compounds, which induce differentiation of colon cancer cells, using a novel dual multiplex assay3. Here we show that MS023, arginine methyl transferase (PRMT) type 1 inhibitor, is a potent inducer of colon cancer cell differentiation with a large therapeutic window. Our findings have a great impact for future research and development of an effective, clinically applicable, differentiation based anti-CRC therapy.
2020-11-27 | GSE142314 | GEO
Project description:Differentiation therapy has been recently revisited as a prospective approach in cancer therapy by targeting the aberrant growth, and repairing the differentiation and cell death programs of cancer cells. However, differentiation therapy of solid tumors is a challenging issue and progress in this field is limited. We performed High Throughput Screening (HTS) using a novel dual multiplex assay to discover compounds, which induce differentiation of human colon cancer cells. Here we show that the protein arginine methyl transferase (PRMT) type 1 inhibitor, MS023, is a potent inducer of colon cancer cell differentiation with a large therapeutic window. Differentiation changes in the highly aggressive human colon cancer cell line (HT-29) were proved by proteomic and genomic approaches. Growth of HT-29 xenograft in nude mice was significantly delayed upon MS023 treatment and immunohistochemistry of tumor indicated differentiation changes. These findings may lead to development of clinically effective anti-cancer drugs based on the mechanism of cancer cell differentiation.
| S-EPMC7676271 | biostudies-literature
Project description:LIN28B induces a differentiation program through CDX2 in colon cancer
| PRJNA695297 | ENA
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:Despite the immense success of immune checkpoint blockade (ICB) in cancer treatment, many tumors, including melanoma, exhibit innate or adaptive resistance. Tumor-intrinsic T-cell deficiency and T-cell dysfunction have been identified as essential factors in the emergence of ICB resistance. Here, we found that protein arginine methyl transferase 1 (PRMT1) expression was inversely correlated with the number and activity of CD8+ T cells within melanoma specimen. PRMT1 deficiency or inhibition with DCPT1061 significantly restrained refractory melanoma growth and increased intratumoral CD8+T cells in vivo. Moreover, PRMT1 deletion in melanoma cells facilitated formation of double-stranded RNA (dsRNA) derived from endogenous retroviral elements (ERVs) and stimulated an intracellular interferon response. Mechanistically, PRMT1 deficiency repressed the expression of DNA methyltransferase 1 (DNMT1) by attenuating modification of H4R3me2a and H3K27ac at enhancer regions of DNMT1, and DNMT1 downregulation consequently activated ERV transcription and the interferon signaling. Importantly, PRMT1 inhibition with DCPT1061 synergized with PD-1 blockade to suppress tumor progression and increase the proportion of CD8+T cells as well as IFNγ+CD8+T cells in vivo. Together, these results reveal an unrecognized role and mechanism of PRMT1 in regulating antitumor T-cell immunity, suggesting PRMT1 inhibition as a potent strategy to increase the efficacy of ICB.
2023-11-07 | GSE240258 | GEO
Project description:Germinal center (GC) B cells undergo cycles of somatic hypermutation and selection, thus increasing their antibody affinity before differentiating into plasma or memory cells. The mechanisms dictating the dynamics of GC B cells are incompletely understood. We show that ablating the Protein arginine methyltransferase 1 (PRMT1) in GC B cells reduces antibody affinity maturation by impairing GC dynamics, as shown by compromised GC expansion, accumulation of CXCR4- B cells, and increased memory B cell differentiation, partly, at the expense of plasma cell production. Furthermore, PRMT1 distinguishes the subset of GC B cells that reenter the GC dark zone after positive selection, in which it is upregulated by Myc in conjunction with mTORC signaling. PRMT1 opposes mature B cell differentiation, as shown by higher plasma cell differentiation of PRMT1-deficient B cells activated ex vivo, a function co-opted by B cell lymphoma cells, in which PRMT1 expression also correlates with Myc expression and outcome.
2023-04-27 | GSE189276 | GEO
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 is known as a regulator of immune function by directly interacting with interferon receptors, methylating STAT1, and promoting B cell and macrophage differentiation by methylating CDK4 or B cell antigen receptor However, the function of PRMT1 as a therapeutic target of cancer remains largely elusive, particularly for its role in cancer immunosurveillance. Here, we performed bulk RNA-seq for CT26, a mouse tumor cell line, after either knocking down of endogeneous Prmt1 or blocking PRMT1 by two specific inhibitors, namely MS023 and GSK3368715.
2023-03-21 | GSE203466 | GEO
Project description:PRMT1 is thought to be responsible for the majority of PRMT activity in Toxoplasma gondii, but its exact function is unknown. We generated T. gondii mutants lacking PRMT1 (∆prmt1) by deletion of the PRMT1 gene. ∆prmt1 parasites exhibit morphological defects during cell division and grow slowly, and this phenotype reverses in the complemented strain ∆prmt::PRMT1mRFP. PRMT1 localizes primarily in the cytoplasm with enrichment at the centrosome, and the strain lacking PRMT1 is unable to segregate progeny accurately. Unlike wild-type and complemented parasites, ∆prmt1 parasites have abnormal daughter buds, perturbed centrosome stoichiometry, and loss of synchronous replication. Whole genome expression profiling demonstrated differences in expression of cell cycle regulated genes in ∆prmt1 relative to the complemented ∆prmt1::PRMT1mRFP and parental wild-type strains, but these changes did not correlate with a specific block in cell cycle. Although PRMT1’s primary biological function was previously proposed to be methylation of histones, our genetic studies suggest that the most critical function of PRMT1 is within the centrosome as a regulator of daughter cell counting to assure the proper replication of the parasite. RNA samples were isolated in triplicates from RH-hxgprt parent strain (W), PRMT1 knockout (K) strain and PRMT1 knockout strain complemented with RFP-tagged PRMT1 protein (C). Parasites were grown for 32h at 37C. Samples were hybridized to the Toxoplasma gondii Affymetrix microarray (ToxoGeneChip: http://ancillary.toxodb.org/docs/Array-Tutorial.html). Hybridization data was preprocessed with Robust Multi-array Average (RMA) and normalized using per chip and per gene median polishing and analyzed using the software package GeneSpring GX (Agilent Technologies).
2015-09-18 | E-GEOD-73177 | biostudies-arrayexpress