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https://www.readbyqxmd.com/read/28806746/selective-small-chemical-inhibitors-of-protein-arginine-methyltransferase-5-with-anti-lung-cancer-activity
#1
Gui-Mei Kong, Min Yu, Zhongping Gu, Zhi Chen, Rui-Ming Xu, Deon O'Bryant, Zhengxin Wang
Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation...
2017: PloS One
https://www.readbyqxmd.com/read/28723619/a-novel-sharpin-prmt5-h3r2me1-axis-is-essential-for-lung-cancer-cell-invasion
#2
Tingxiong Fu, Xiuwei Lv, Qingzhi Kong, Changjing Yuan
SHARPIN (Shank-associated RH domain interacting protein) is the main component of the linear ubiquitin chain activation complex (LUBAC). SHARPIN is involved in regulating inflammation and cancer progression. However, whether SHARPIN plays an important role in lung cancer metastasis and the potential underlying mechanism are still unknown. Here, for the first time, we reported that SHARPIN expression is closely related to lung cancer progression. Moreover, SHARPIN plays a central role in controlling lung cancer cell metastasis...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28650658/potent-selective-and-cell-active-protein-arginine-methyltransferase-5-prmt5-inhibitor-developed-by-structure-based-virtual-screening-and-hit-optimization
#3
Ruifeng Mao, Jingwei Shao, Kongkai Zhu, Yuanyuan Zhang, Hong Ding, Chenhua Zhang, Zhe Shi, Hualiang Jiang, Dequn Sun, Wenhu Duan, Cheng Luo
PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0...
July 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28591716/adapting-alphalisa-high-throughput-screen-to-discover-a-novel-small-molecule-inhibitor-targeting-protein-arginine-methyltransferase-5-in-pancreatic-and-colorectal-cancers
#4
Lakshmi Prabhu, Han Wei, Lan Chen, Özlem Demir, George Sandusky, Emily Sun, John Wang, Jessica Mo, Lifan Zeng, Melissa Fishel, Ahmad Safa, Rommie Amaro, Murray Korc, Zhong-Yin Zhang, Tao Lu
Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28461757/novel-role-of-granulocyte-macrophage-colony-stimulating-factor-antitumor-effects-through-inhibition-of-epithelial-to-mesenchymal-transition-in-esophageal-cancer
#5
Jingxin Zhang, Qiqi Liu, Lili Qiao, Pingping Hu, Guodong Deng, Ning Liang, Jian Xie, Hui Luo, Jiandong Zhang
PURPOSE: Recent studies demonstrate the possible antitumor effects of granulocyte-macrophage colony-stimulating factor (GM-CSF); however, the exact mechanism is still unclear. The aim of our study was to analyze the effects of GM-CSF on multiple biological functions of human esophageal cancer (EC) cell lines and to explore the potential mechanism of its antitumor effects. MATERIALS AND METHODS: Eca109/9706 human EC cells were examined. Cell proliferation, apoptosis, and migration were analyzed using cell proliferation assay, flow cytometry, and transwell assay, respectively...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28397890/discovery-and-optimization-of-selective-inhibitors-of-protein-arginine-methyltransferase-5-by-docking-based-virtual-screening
#6
Yan Ye, Bidong Zhang, Ruifeng Mao, Chenhua Zhang, Yulan Wang, Jing Xing, Yu-Chih Liu, Xiaomin Luo, Hong Ding, Yaxi Yang, Bing Zhou, Hualiang Jiang, Kaixian Chen, Cheng Luo, Mingyue Zheng
Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT enzyme critical for diverse cellular processes and different types of cancers. Many efforts have been made to discover novel scaffold PRMT5 inhibitors. Herein, we report the discovery of DC_P33 as a hit compound of PRMT5 inhibitor, identified by molecular docking based virtual screening and (3)H-labeled radioactive methylation assays. Structure-activity relationship (SAR) analysis was performed on the analogs of DC_P33 and then structural modifications were done to improve its activity...
May 3, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28349379/ulva-pertusa-lectin-1-delivery-through-adenovirus-vector-affects-multiple-signaling-pathways-in-cancer-cells
#7
Gongchu Li, Zhenzhen Zhao, Bingbing Wu, Qunshu Su, Liqin Wu, Xinyan Yang, Jing Chen
Ulva pertusa lectin 1 (UPL1) is a N-acetyl-D-glucosamine (GlcNAc) binding lectin in marine green alga Ulva pertusa. Exogenous UPL1 colocalized with protein arginine methyltransferase 5 (PRMT5), methylosome protein 50 (MEP50), β-actin and β-tubulin, indicating the interaction of UPL1 with the methylosome and cytoskeleton. UPL1 delivery through adenovirus vector (Ad-UPL1) dramatically induced extracellularly regulated protein kinases 1/2 (ERK1/2) phosphorylation in liver cancer cell lines BEL-7404 and Huh7...
August 2017: Glycoconjugate Journal
https://www.readbyqxmd.com/read/28302565/inhibition-of-prmt5-suppresses-osteoclast-differentiation-and-partially-protects-against-ovariectomy-induced-bone-loss-through-downregulation-of-cxcl10-and-rsad2
#8
Yonghui Dong, Chao Song, Yuting Wang, Zuowei Lei, Fei Xu, Hanfeng Guan, Anmin Chen, Feng Li
Protein arginine methyltransferase 5 (PRMT5) is an arginine methylation methyltransferase that regulates various physiological processes. Abnormal PRMT5 activity has been reported in inflammation and various types of cancers. Because osteoclast differentiation is characterized by the activation of inflammation-related pathways, we speculated that PRMT5 may play a role in this process. In the present study, we found that PRMT5 was upregulated during osteoclast differentiation. Knockdown of PRMT5 with siRNA in bone marrow mononuclear cells (BMMs) resulted in inhibition of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation...
March 14, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28271477/the-structure-and-function-of-the-prmt5-mep50-complex
#9
Stephen Antonysamy
Protein arginine methyltransferase 5 (PRMT5) plays multiple roles in cellular processes at different stages of the cell cycle in a tissue specific manner. PRMT5 in complex with MEP50/p44/WDR77 associates with a plethora of partner proteins to symmetrically dimethylate arginine residues on target proteins in both the nucleus and the cytoplasm. Overexpression of PRMT5 has been observed in several cancers, making it an attractive drug target. The structure of the 453 kDa heterooctameric PRMT5:MEP50 complex bound to an S-adenosylmethionine analog and a substrate peptide provides valuable insights into this intriguing target...
2017: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/28215224/the-complex-role-of-the-znf224-transcription-factor-in-cancer
#10
REVIEW
E Cesaro, G Sodaro, G Montano, M Grosso, A Lupo, P Costanzo
ZNF224 is a member of the Kruppel-associated box zinc finger proteins (KRAB-ZFPs) family. It was originally identified as a transcriptional repressor involved in gene-specific silencing through the recruitment of the corepressor KAP1, chromatin-modifying activities, and the arginine methyltransferase PRMT5 on the promoter of its target genes. Recent findings indicate that ZNF224 can behave both as a tumor suppressor or an oncogene in different human cancers. The transcriptional regulatory properties of ZNF224 in these systems appear to be complex and influenced by specific sets of interactors...
2017: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/28107179/nuclear-prmt5-cyclin-d1-and-il-6-are-associated-with-poor-outcome-in-oropharyngeal-squamous-cell-carcinoma-patients-and-is-inversely-associated-with-p16-status
#11
Bhavna Kumar, Arti Yadav, Nicole V Brown, Songzhu Zhao, Michael J Cipolla, Paul E Wakely, Alessandra C Schmitt, Robert A Baiocchi, Theodoros N Teknos, Matthew Old, Pawan Kumar
Protein arginine methyltransferase-5 (PRMT5) plays an important role in cancer progression by repressing the expression of key tumor suppressor genes via the methylation of transcriptional factors and chromatin-associated proteins. However, very little is known about the expression and biological role of PRMT5 in head and neck cancer. In this study, we examined expression profile of PRMT5 at subcellular levels in oropharyngeal squamous cell carcinoma (OPSCC) and assessed its correlation with disease progression and patient outcome...
February 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28087667/prmt5-selective-inhibitors-suppress-inflammatory-t-cell-responses-and-experimental-autoimmune-encephalomyelitis
#12
Lindsay M Webb, Stephanie A Amici, Kyle A Jablonski, Himanshu Savardekar, Amanda R Panfil, Linsen Li, Wei Zhou, Kevin Peine, Vrajesh Karkhanis, Eric M Bachelder, Kristy M Ainslie, Patrick L Green, Chenglong Li, Robert A Baiocchi, Mireia Guerau-de-Arellano
In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking...
February 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28074910/myosin-phosphatase-and-rhoa-activated-kinase-modulate-arginine-methylation-by-the-regulation-of-protein-arginine-methyltransferase-5-in-hepatocellular-carcinoma-cells
#13
Adrienn Sipos, Judit Iván, Bálint Bécsi, Zsuzsanna Darula, István Tamás, Dániel Horváth, Katalin F Medzihradszky, Ferenc Erdődi, Beáta Lontay
Myosin phosphatase (MP) holoenzyme is a protein phosphatase-1 (PP1) type Ser/Thr specific enzyme that consists of a PP1 catalytic (PP1c) and a myosin phosphatase target subunit-1 (MYPT1). MYPT1 is an ubiquitously expressed isoform and it targets PP1c to its substrates. We identified the protein arginine methyltransferase 5 (PRMT5) enzyme of the methylosome complex as a MYPT1-binding protein uncovering the nuclear MYPT1-interactome of hepatocellular carcinoma cells. It is shown that PRMT5 is regulated by phosphorylation at Thr80 by RhoA-associated protein kinase and MP...
January 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27714957/discovery-of-selective-protein-arginine-methyltransferase-5-inhibitors-and-biological-evaluations
#14
Sen Ji, Shuang Ma, Wen-Jing Wang, Shen-Zhen Huang, Tian-Qi Wang, Rong Xiang, Yi-Guo Hu, Qiang Chen, Lin-Li Li, Sheng-Yong Yang
Protein arginine methyltransferase 5 (PRMT5) is an important protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine resides on histones or non-histone substrate proteins. It has been thought as a promising target for many diseases, particularly cancer. Despite the potential applications of PRMT5 inhibitors in cancer treatment, very few of PRMT5i have been publicly reported. In this investigation, virtual screening and structure-activity relationship studies were carried out to discover novel PRMT5i, which finally led to the identification of a number of new PRMT5i...
April 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/27708221/prmt5-competitively-binds-to-cdk4-to-promote-g1-s-transition-upon-glucose-induction-in-hepatocellular-carcinoma
#15
Hao Yang, Xiaoping Zhao, Li Zhao, Liu Liu, Jiajin Li, Wenzhi Jia, Jianjun Liu, Gang Huang
Although cancer cells are known to be "addicted" to glucose, the effect of glucose in proliferation of these cells remains elusive. Here, we report that upon glucose induction, protein arginine methyltransferase 5 (PRMT5) exerts a profound effect on the G1-S cell cycle progression via directly interacting with cyclin dependent kinase 4 (CDK4) in hepatocellular carcinoma (HCC). Upregulation of both PRMT5 and CDK4 predicts more malignant characteristics in human HCC tissues. Mechanistically, glucose promotes the interaction between PRMT5 and CDK4, which leads to activation of CDK4-RB-E2F-mediated transcription via releasing CDKN2A from CDK4...
November 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27546619/protein-arginine-methyltransferase-5-functions-as-an-epigenetic-activator-of-the-androgen-receptor-to-promote-prostate-cancer-cell-growth
#16
X Deng, G Shao, H-T Zhang, C Li, D Zhang, L Cheng, B D Elzey, R Pili, T L Ratliff, J Huang, C-D Hu
Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells...
March 2, 2017: Oncogene
https://www.readbyqxmd.com/read/27315569/protein-arginine-methyltransferase-5-is-associated-with-malignant-phenotype-and-peritoneal-metastasis-in-gastric-cancer
#17
Mitsuro Kanda, Dai Shimizu, Tsutomu Fujii, Haruyoshi Tanaka, Masahiro Shibata, Naoki Iwata, Masamichi Hayashi, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera
Identification of novel gastric cancer (GC)-related molecules is necessary to improve management of patients with GC in both diagnostic and therapeutic aspects. The aim of the present study was to determine whether protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in the progression of GC and whether it serves as a novel diagnostic marker and therapeutic target. We conducted global expression profiling of GC cell lines and RNA interference experiments to evaluate the effect of PRMT5 expression on the phenotype of GC cells...
September 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27270440/a-tgf%C3%AE-prmt5-mep50-axis-regulates-cancer-cell-invasion-through-histone-h3-and-h4-arginine-methylation-coupled-transcriptional-activation-and-repression
#18
H Chen, B Lorton, V Gupta, D Shechter
Protein arginine methyltransferase 5 (PRMT5) complexed with MEP50/WDR77 catalyzes arginine methylation on histones and other proteins. PRMT5-MEP50 activity is elevated in cancer cells and its expression is highly correlated with poor prognosis in many human tumors. We demonstrate that PRMT5-MEP50 is essential for transcriptional regulation promoting cancer cell invasive phenotypes in lung adenocarcinoma, lung squamous cell carcinoma and breast carcinoma cancer cells. RNA-Seq transcriptome analysis demonstrated that PRMT5 and MEP50 are required to maintain expression of metastasis and Epithelial-to-mesenchymal transition (EMT) markers and to potentiate an epigenetic mechanism of the TGFβ response...
January 19, 2017: Oncogene
https://www.readbyqxmd.com/read/27242039/aflatoxin-b1-induced-upregulation-of-protein-arginine-methyltransferase-5-in-human-cell-lines
#19
Md Sajid Ghufran, Krishna Ghosh, Santosh R Kanade
The exposure of naturally occurring mycotoxins affects human health and play a vital role in cancer initiation and progression. Aflatoxin B1 is a difuranocoumarin mycotoxin, classified as a group I carcinogen. The present study was conducted to assess the effect of aflatoxin B1 on epigenetic regulatory proteins. The protein arginine methyltransferase 5 expression was induced upon aflatoxin B1 treatment in a dose and time dependent manner. Further global arginine methylation was also increased in the same manner...
September 1, 2016: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/27183006/erg-signaling-in-prostate-cancer-is-driven-through-prmt5-dependent-methylation-of-the-androgen-receptor
#20
Zineb Mounir, Joshua M Korn, Thomas Westerling, Fallon Lin, Christina A Kirby, Markus Schirle, Gregg McAllister, Greg Hoffman, Nadire Ramadan, Anke Hartung, Yan Feng, David Randal Kipp, Christopher Quinn, Michelle Fodor, Jason Baird, Marie Schoumacher, Ronald Meyer, James Deeds, Gilles Buchwalter, Travis Stams, Nicholas Keen, William R Sellers, Myles Brown, Raymond A Pagliarini
The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells...
2016: ELife
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