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https://www.readbyqxmd.com/read/27714957/discovery-of-selective-protein-arginine-methyltransferase-5-inhibitors-and-biological-evaluations
#1
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...
October 7, 2016: 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
#2
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...
September 30, 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
#3
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...
August 22, 2016: Oncogene
https://www.readbyqxmd.com/read/27315569/protein-arginine-methyltransferase-5-is-associated-with-malignant-phenotype-and-peritoneal-metastasis-in-gastric-cancer
#4
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
#5
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...
June 6, 2016: Oncogene
https://www.readbyqxmd.com/read/27242039/aflatoxin-b1-induced-upregulation-of-protein-arginine-methyltransferase-5-in-human-cell-lines
#6
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
#7
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
https://www.readbyqxmd.com/read/27068473/mtap-deletions-in-cancer-create-vulnerability-to-targeting-of-the-mat2a-prmt5-riok1-axis
#8
Katya Marjon, Michael J Cameron, Phong Quang, Michelle F Clasquin, Everton Mandley, Kaiko Kunii, Michael McVay, Sung Choe, Andrew Kernytsky, Stefan Gross, Zenon Konteatis, Joshua Murtie, Michelle L Blake, Jeremy Travins, Marion Dorsch, Scott A Biller, Kevin M Marks
Homozygous deletions of p16/CDKN2A are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including methylthioadenosine phosphorylase (MTAP). Here, we used shRNA screening and identified the metabolic enzyme, methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. The MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss...
April 19, 2016: Cell Reports
https://www.readbyqxmd.com/read/27041824/the-role-of-protein-arginine-methyltransferases-in-inflammatory-responses
#9
REVIEW
Ji Hye Kim, Byong Chul Yoo, Woo Seok Yang, Eunji Kim, Sungyoul Hong, Jae Youl Cho
Protein arginine methyltransferases (PRMTs) mediate the methylation of a number of protein substrates of arginine residues and serve critical functions in many cellular responses, including cancer development, progression, and aggressiveness, T-lymphocyte activation, and hepatic gluconeogenesis. There are nine members of the PRMT family, which are divided into 4 types (types I-IV). Although most PRMTs do not require posttranslational modification (PTM) to be activated, fine-tuning modifications, such as interactions between cofactor proteins, subcellular compartmentalization, and regulation of RNA, via micro-RNAs, seem to be required...
2016: Mediators of Inflammation
https://www.readbyqxmd.com/read/26990556/anguilla-japonica-lectin-1-delivery-through-adenovirus-vector-induces-apoptotic-cancer-cell-death-through-interaction-with-prmt5
#10
Gongchu Li, Yajun Gao, Lianzhen Cui, Liqin Wu, Xinyan Yang, Jing Chen
INTRODUCTION: Our previous studies have demonstrated that through adenovirus mediated gene delivery, various exogenously expressed lectins elicited cytotoxicity to cancer cells, utilizing protein arginine methyltransferase 5 (PRMT5) as a common binding target. AIMS: In this work, a FLAG tagged Anguilla japonica lectin 1 (AJL1) expression cassette was genetically harbored in a replication-defective adenovirus genome, forming Ad.FLAG-AJL1. The exogenous AJL1 induced cytotoxicity and the underlying mechanism were analyzed...
March 17, 2016: Journal of Gene Medicine
https://www.readbyqxmd.com/read/26988096/gli-pathogenesis-related-1-functions-as-a-tumor-suppressor-in-lung-cancer
#11
Xiumei Sheng, Nathan Bowen, Zhengxin Wang
BACKGROUND: GLI pathogenesis-related 1 (GLIPR1) was originally identified in glioblastomas and its expression was also found to be down-regulated in prostate cancer. Functional studies revealed both growth suppression and proapoptotic activities for GLIPR1 in multiple cancer cell lines. GLIPR1's role in lung cancer has not been investigated. Protein arginine methyltransferase 5 (PRMT5) is a protein arginine methyltransferase and forms a stoichiometric complex with the WD repeat domain 77 (WDR77) protein...
2016: Molecular Cancer
https://www.readbyqxmd.com/read/26912361/disordered-methionine-metabolism-in-mtap-cdkn2a-deleted-cancers-leads-to-dependence-on-prmt5
#12
Konstantinos J Mavrakis, E Robert McDonald, Michael R Schlabach, Eric Billy, Gregory R Hoffman, Antoine deWeck, David A Ruddy, Kavitha Venkatesan, Jianjun Yu, Gregg McAllister, Mark Stump, Rosalie deBeaumont, Samuel Ho, Yingzi Yue, Yue Liu, Yan Yan-Neale, Guizhi Yang, Fallon Lin, Hong Yin, Hui Gao, D Randal Kipp, Songping Zhao, Joshua T McNamara, Elizabeth R Sprague, Bing Zheng, Ying Lin, Young Shin Cho, Justin Gu, Kenneth Crawford, David Ciccone, Alberto C Vitari, Albert Lai, Vladimir Capka, Kristen Hurov, Jeffery A Porter, John Tallarico, Craig Mickanin, Emma Lees, Raymond Pagliarini, Nicholas Keen, Tobias Schmelzle, Francesco Hofmann, Frank Stegmeier, William R Sellers
5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity...
March 11, 2016: Science
https://www.readbyqxmd.com/read/26912360/mtap-deletion-confers-enhanced-dependency-on-the-prmt5-arginine-methyltransferase-in-cancer-cells
#13
Gregory V Kryukov, Frederick H Wilson, Jason R Ruth, Joshiawa Paulk, Aviad Tsherniak, Sara E Marlow, Francisca Vazquez, Barbara A Weir, Mark E Fitzgerald, Minoru Tanaka, Craig M Bielski, Justin M Scott, Courtney Dennis, Glenn S Cowley, Jesse S Boehm, David E Root, Todd R Golub, Clary B Clish, James E Bradner, William C Hahn, Levi A Garraway
The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A...
March 11, 2016: Science
https://www.readbyqxmd.com/read/26893451/mtap-deletion-promotes-cancer-cell-dependence-on-prmt5
#14
(no author information available yet)
InMTAP-deficient cancer cells, PRMT5 expression and activity is preferentially required for cell growth.
April 2016: Cancer Discovery
https://www.readbyqxmd.com/read/26789238/small-molecule-inhibitors-of-protein-arginine-methyltransferases
#15
REVIEW
Hao Hu, Kun Qian, Meng-Chiao Ho, Y George Zheng
INTRODUCTION: Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery. AREAS COVERED: The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5...
2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/26759235/arginine-methylation-of-srebp1a-via-prmt5-promotes-de-novo-lipogenesis-and-tumor-growth
#16
Liu Liu, Xiaoping Zhao, Li Zhao, Jiajin Li, Hao Yang, Zongping Zhu, Jianjun Liu, Gang Huang
Dysregulation of the sterol regulatory element-binding transcription factors sterol regulatory element-binding protein (SREBP) and SREBF activates de novo lipogenesis to high levels in cancer cells, a critical event in driving malignant growth. In this study, we identified an important posttranslational mechanism by which SREBP1a is regulated during metabolic reprogramming in cancer cells. Mass spectrometry revealed protein arginine methyltransferase 5 (PRMT5) as a binding partner of SREBP1a that symmetrically dimethylated it on R321, thereby promoting transcriptional activity...
March 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/26658161/the-e3-ubiquitin-ligase-chip-mediates-ubiquitination-and-proteasomal-degradation-of-prmt5
#17
Huan-Tian Zhang, Ling-Fei Zeng, Qing-Yu He, W Andy Tao, Zhen-Gang Zha, Chang-Deng Hu
Protein arginine methyltransferase 5 (PRMT5) is an important member of the protein arginine methyltransferase family that regulates many cellular processes through epigenetic control of target gene expression. Because of its overexpression in a number of human cancers and its essential role in cell proliferation, transformation, and cell cycle progression, PRMT5 has been recently proposed to function as an oncoprotein in cancer cells. However, how its expression is regulated in cancer cells remains largely unknown...
February 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/26597461/methylation-of-tumor-suppressor-gene-cdh13-and-shp1-promoters-and-their-epigenetic-regulation-by-the-uhrf1-prmt5-complex-in-endometrial-carcinoma
#18
Yan Sheng, Hongtao Wang, Dongchen Liu, Cheng Zhang, Yupeng Deng, Fan Yang, Tingguo Zhang, Cuijuan Zhang
OBJECTIVE: Epigenetic changes in cancer and precancerous lesions could be utilized as biomarkers for cancer early detection. This study aims to investigate the novel biomarkers in endometrial carcinoma, and explore their epigenetic regulation. METHODS: Methylation of six tumor suppressor genes (CDH13, SHP1, HIN1, DKK3, CTNNA1 and PCDH8) was evaluated in 155 endometrium samples. Changes of methylation and mRNA expression after treatment with 5-Aza-2'-deoxycytidine (5-Aza-CdR) or/and trichostatin A (TSA) were investigated by MSP and qRT-PCR respectively...
January 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/26536822/the-dual-epigenetic-role-of-prmt5-in-acute-myeloid-leukemia-gene-activation-and-repression-via-histone-arginine-methylation
#19
S S Tarighat, R Santhanam, D Frankhouser, H S Radomska, H Lai, M Anghelina, H Wang, X Huang, L Alinari, A Walker, M A Caligiuri, C M Croce, L Li, R Garzon, C Li, R A Baiocchi, G Marcucci
Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the protein's role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3. As Sp1 is also a bona fide target of miR-29b, the miR silencing resulted in increased Sp1...
April 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/26420673/interplay-between-arginine-methylation-and-ubiquitylation-regulates-klf4-mediated-genome-stability-and-carcinogenesis
#20
Dong Hu, Mert Gur, Zhuan Zhou, Armin Gamper, Mien-Chie Hung, Naoya Fujita, Li Lan, Ivet Bahar, Yong Wan
KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4-repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5...
September 30, 2015: Nature Communications
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