scholarly journals SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

2017 ◽  
Vol 128 (1) ◽  
pp. 517-530 ◽  
Author(s):  
Hironari Tamiya ◽  
Hyungsoo Kim ◽  
Oleksiy Klymenko ◽  
Heejung Kim ◽  
Yongmei Feng ◽  
...  
Keyword(s):  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Melanoma Growth ◽  
Protein Arginine Methyltransferase 5

scholarly journals Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sara Busacca ◽  
Qi Zhang ◽  
Annabel Sharkey ◽  
Alan G. Dawson ◽  
David A. Moore ◽  
...  
Keyword(s):  
Small Molecule ◽  
Selective Vulnerability ◽  
Dependent Manner ◽  
Histone H4 ◽  
Wild Type ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Methylthioadenosine Phosphorylase ◽  
Protein Arginine Methyltransferase 5

AbstractWe hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

scholarly journals Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors

2019 ◽  
Vol 10 (7) ◽  
pp. 1033-1038 ◽  
Author(s):  
Hong Lin ◽  
Min Wang ◽  
Yang W. Zhang ◽  
Shuilong Tong ◽  
Raul A. Leal ◽  
...  
Keyword(s):  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Protein Arginine Methyltransferase 5

scholarly journals Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers

2019 ◽  
Vol 8 (5) ◽  
pp. 2414-2428 ◽  
Author(s):  
Mathilde Vinet ◽  
Samyuktha Suresh ◽  
Virginie Maire ◽  
Clarisse Monchecourt ◽  
Fariba Némati ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Triple Negative ◽  
Breast Cancers ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Novel Therapeutic ◽  
Protein Arginine Methyltransferase 5

Lead induces the up-regulation of the protein arginine methyltransferase 5 possibly by its promoter demethylation

2018 ◽  
Vol 475 (16) ◽  
pp. 2653-2666 ◽  
Author(s):  
Krishna Ghosh ◽  
Biji Chatterjee ◽  
Santosh R. Kanade
Keyword(s):  
Cpg Island ◽  
Proximal Region ◽  
Dependent Manner ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Arginine Residues ◽  
Pb Exposure ◽  
Mcf 7 ◽  
Protein Arginine Methyltransferase 5

The studies on lead (Pb) exposure linking to epigenetic modulations are caused by its differential actions on global DNA methylation and histone modifications. These epigenetic changes may result in increased accessibility of the transcription factors to promoter DNA-binding elements leading to activation and expression of the gene. The protein arginine methyltransferase 5 (PRMT5) and its partner methylosome protein 50 (MEP50) together catalyze the mono- and symmetric dimethylation of arginine residues in many histone and non-histone protein substrates. Moreover, it is overexpressed in many forms of cancer. In the present study, the effects of Pb on the PRMT5 and MEP50 expression and formation of the symmetrically dimethylated arginine (SDMA), the catalytic product of the PRMT5–MEP50 complex were analyzed in vitro after exposing the A549 and MCF-7 cells. The results show that exposure to 0.1 and 1 µM of Pb strongly enhanced the expression of both PRMT5 and MEP50 transcript and protein leading to increased SDMA levels globally with H4R3 being increasingly symmetrically dimethylated in a dose-dependent manner after 48 h of Pb exposure in both cell types. The methylation-specific PCR also revealed that the CpG island present on the PRMT5 promoter proximal region was increasingly demethylated as the dose of Pb increased in a 48-h exposure window in both cells, with MCF-7 being more responsive to Pb-mediated PRMT5 promoter demethylation. The bisulfite sequencing confirmed this effect. The findings therefore indicate that Pb exposure increasing the PRMT5 expression might be one of the contributing epigenetic factors in the lead-mediated disease processes as PRMT5 has a versatile role in cellular functions and oncogenesis.

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