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.

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.

scholarly journals The LIM Protein AJUBA Recruits Protein Arginine Methyltransferase 5 To Mediate SNAIL-Dependent Transcriptional Repression

2008 ◽  
Vol 28 (10) ◽  
pp. 3198-3207 ◽  
Author(s):  
Zhaoyuan Hou ◽  
Hongzhuang Peng ◽  
Kasirajan Ayyanathan ◽  
Kai-Ping Yan ◽  
Ellen M. Langer ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Epithelial Mesenchymal Transition ◽  
Arginine Methylation ◽  
Proximal Promoter ◽  
Dependent Manner ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Mesenchymal Transition ◽  
E Cadherin ◽  
Protein Arginine Methyltransferase 5

ABSTRACT The SNAIL transcription factor contains C-terminal tandem zinc finger motifs and an N-terminal SNAG repression domain. The members of the SNAIL family have recently emerged as major contributors to the processes of development and metastasis via the regulation of epithelial-mesenchymal transition events during embryonic development and tumor progression. However, the mechanisms by which SNAIL represses gene expression are largely undefined. Previously we demonstrated that the AJUBA family of LIM proteins function as corepressors for SNAIL and, as such, may serve as a platform for the assembly of chromatin-modifying factors. Here, we describe the identification of the protein arginine methyltransferase 5 (PRMT5) as an effector recruited to SNAIL through an interaction with AJUBA that functions to repress the SNAIL target gene, E-cadherin. PRMT5 binds to the non-LIM region of AJUBA and is translocated into the nucleus in a SNAIL- and AJUBA-dependent manner. The depletion of PRMT5 in p19 cells stimulates E-cadherin expression, and the SNAIL, AJUBA, and PRMT5 ternary complex can be found at the proximal promoter region of the E-cadherin gene, concomitant with increased arginine methylation of histones at the locus. Together, these data suggest that PRMT5 is an effector of SNAIL-dependent gene repression.

scholarly journals Protein Arginine Methyltransferase 5 (Prmt5) Promotes Gene Expression of Peroxisome Proliferator-Activated Receptor γ2 (PPARγ2) and Its Target Genes during Adipogenesis

2012 ◽  
Vol 26 (4) ◽  
pp. 583-597 ◽  
Author(s):  
Scott E. LeBlanc ◽  
Silvana Konda ◽  
Qiong Wu ◽  
Yu-Jie Hu ◽  
Christine M. Oslowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Adipogenic Differentiation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adipogenic Gene ◽  
Protein Arginine Methyltransferase 5

Abstract Regulation of adipose tissue formation by adipogenic-regulatory proteins has long been a topic of interest given the ever-increasing health concerns of obesity and type 2 diabetes in the general population. Differentiation of precursor cells into adipocytes involves a complex network of cofactors that facilitate the functions of transcriptional regulators from the CCATT/enhancer binding protein, and the peroxisome proliferator-activated receptor (PPAR) families. Many of these cofactors are enzymes that modulate the structure of chromatin by altering histone-DNA contacts in an ATP-dependent manner or by posttranslationally modifying the histone proteins. Here we report that inhibition of protein arginine methyltransferase 5 (Prmt5) expression in multiple cell culture models for adipogenesis prevented the activation of adipogenic genes. In contrast, overexpression of Prmt5 enhanced adipogenic gene expression and differentiation. Chromatin immunoprecipitation experiments indicated that Prmt5 binds to and dimethylates histones at adipogenic promoters. Furthermore, the presence of Prmt5 promoted the binding of ATP-dependent chromatin-remodeling enzymes and was required for the binding of PPARγ2 at PPARγ2-regulated promoters. The data indicate that Prmt5 acts as a coactivator for the activation of adipogenic gene expression and promotes adipogenic differentiation.

scholarly journals Protein Arginine Methyltransferase 5 Promotes the Migration of AML Cells by Regulating the Expression of Leukocyte Immunoglobulin-Like Receptor B4

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Lu Zhao ◽  
Bingqing Cheng ◽  
Jie Xiong ◽  
Dan Ma ◽  
Xin Liu ◽  
...  
Keyword(s):  
Leukemic Cells ◽  
Clinical Samples ◽  
Invasive Ability ◽  
Protein Arginine Methyltransferase ◽  
Migration Ability ◽  
Arginine Methyltransferase ◽  
Protein Levels ◽  
Proliferation And Differentiation ◽  
Protein Arginine Methyltransferase 5

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults with poor prognosis. Especially for AML-M5 type, due to the strong cell migration ability, the possibility of extramedullary invasion is large and widespread, which leads to poor therapeutic effect. Previous studies have found that protein arginine methyltransferase 5 (PRMT5) could promote the proliferation and differentiation of leukemic cells in AML, but its regulation on the invasive ability of AML cells remains unclear. This study was designed to explore the role of PRMT5 in regulating the invasion of AML cells and to investigate the mechanisms. Patient samples were collected for detection of PRMT5 expression level. AML cells were used for exploring the function of PRMT5. The results of clinical samples showed that the expression of PRMT5 was significantly increased in newly diagnosed and recurrent AML patients, and the expression of leukocyte immunoglobulin-like receptor B4 (LILRB4) was positively correlated with the level of PRMT5. In the cell experiment in vitro, we found that when PRMT5 was knocked down, the invasion, migration, and adhesion capacities of MV-4-11 cells and THP-1 cells were decreased, and the mRNA and protein levels of LILRB4 were also decreased. Moreover, we screened related signaling pathways and found that PRMT5 affected the expression of downstream LILRB4 by activating mTOR pathway, which in turn enhanced the invasive ability of AML cells. Taken together, PRMT5 plays an important role in the invasion of AML, which acts via regulating the expression of LILRB4. PRMT5 could act as a potential therapeutic candidate for AML.

scholarly journals Protein Arginine Methyltransferase 5 as a Therapeutic Target for KRAS Mutated Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2091
Author(s):  
David Shifteh ◽  
Tzuriel Sapir ◽  
Moshe Pahmer ◽  
Adam Haimowitz ◽  
Sanjay Goel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Wild Type ◽  
Kras Gene ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Cellular Processes ◽  
Cycle Arrest ◽  
Cancer Types ◽  
First Time ◽  
Protein Arginine Methyltransferase 5

Nearly 45% of colorectal cancer (CRC) patients harbor a mutation in their KRAS gene for which, despite many years of research, there are still no targeted therapies available. Protein Arginine Methyltransferase 5 (PRMT5) is a transcription regulator for multiple cellular processes that is currently being tested as a potential target in several cancer types. PRMT5 has been previously shown to be overexpressed in approximately 75% of CRC patient tumor samples, as well as negatively correlated with CRC patient survival. Here, we provide evidence that PRMT5 can act as a surrogate target for mutated KRAS in CRC. Our findings show that PRMT5 expression is upregulated, as well as positively correlated with KRAS expression, in CRC patient datasets. Moreover, our results reveal that PRMT5 is further overexpressed in KRAS mutant CRC cells when compared to KRAS wild type (WT) CRC cells at both the transcriptional and translational levels. Additionally, our data demonstrate that this further overexpression of PRMT5 in the KRAS mutant CRC cells affects an even greater degree of growth inhibition, apoptosis, and cell cycle arrest, following treatment with PRMT5 inhibitor, when compared to the KRAS WT CRC cells. Our research therefore suggests for the first time that PRMT5 and KRAS may crosstalk, and thus, PRMT5 can potentially be used as a surrogate target for mutated KRAS in CRC.

scholarly journals Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasaman Barekatain ◽  
Jeffrey J. Ackroyd ◽  
Victoria C. Yan ◽  
Sunada Khadka ◽  
Lin Wang ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Homozygous Deletion ◽  
In Vitro Models ◽  
Arginine Methyltransferase ◽  
Human Glioblastoma ◽  
Primary Glioblastoma ◽  
Methylthioadenosine Phosphorylase ◽  
Metabolomic Profiling

AbstractHomozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.

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
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