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Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M Najjar, Mary M Lee, Joae Qiong Wu
Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionallyly by symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3, or at the post-translational level by methylation of non-histone target proteins. While emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well defined. We investigated the role of PRMT5 in promoting high fat-induced hepatic steatosis. High fat diet up-regulated PRMT5 levels in the liver, but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue...
May 17, 2018: Journal of Biological Chemistry
Alexander Bowitch, Kerry L Michaels, Michael C Yu, Denise M Ferkey
G protein-coupled receptors are 7-pass transmembrane receptors that couple to heterotrimeric G proteins to mediate cellular responses to a diverse array of stimuli. Understanding the mechanisms that regulate G protein-coupled receptors is crucial to manipulating their signaling for therapeutic benefit. One key regulatory mechanism that contributes to the functional diversity of many signaling proteins is post-translational modification. Whereas phosphorylation remains the best studied of such modifications, arginine methylation by protein arginine methyltransferases is emerging as a key regulator of protein function...
May 14, 2018: G3: Genes—Genomes—Genetics
Ju-Yeon Jeon, Jee San Lee, Eun-Ran Park, Yan Nan Shen, Mi-Yeun Kim, Hyun-Jin Shin, Hyun-Yoo Joo, Eung-Ho Cho, Sun Mi Moon, Ui Sup Shin, Sun Hoo Park, Chul Ju Han, Dong Wook Choi, Man Bock Gu, Sang-Bum Kim, Kee-Ho Lee
Protein arginine methyltransferase 5 (PRMT5) is a protein that catalyzes transfer of methyl groups to the arginine residues of proteins and is involved in diverse cellular and biological responses. While the participation of PRMT5 in cancer progression has been increasingly documented, its association with the invasive phenotype currently remains poorly understood. In the present study, we revealed that PRMT5 is overexpressed in human hepatocellular carcinoma (HCC) and in colon cancer and its depletion leads to the suppression of cell invasive activity via the reduction of the expression of MMP-2...
April 25, 2018: Oncology Reports
Aniket Gupta, Jogendra Kumar, Sukalyan Bhadra
A highly regioselective de-aryloxylative amination of O- or N-chelating group-functionalized 2-aryloxy quinolines has been accomplished by means of a copper catalyst. The chelating functional groups of the substrate play a crucial role in directing the C-2-selective amination process, which proceeds through a novel aromatic nucleophilic substitution of the aryloxy group. The methodology provides expedient access to an important class of functionalized 2-aminoquinolines (up to 88% isolated yield) and was successfully applied for the synthesis of a key fragment of an important bioactive PRMT5 inhibitor...
May 8, 2018: Organic & Biomolecular Chemistry
Shu-Hong Dong, Xing Wang, San-Chun Tian, Neng-Qian Ma, Xin-Yang Zhang, Yapeng Liu, Bao-Lai Zhang, Yong-Jie Wu
Protein arginine methyltransferase 5 (PRMT5), a type II PRMT, is highly expressed in several types of tumors including cervical cancer. Arginine methyltransferase inhibitor 1 (AMI-1) inhibits solid tumors by targeting PRMT5. However, the effect of AMI-1 on cervical cancer is still unknown. In this study, we provided the first evidence that AMI-1 reduced cervical cancer cell proliferation, colony formation and promoted cell apoptosis in vitro. Suppression of tumorigenicity was also confirmed in vivo. Mechanistic studies revealed that AMI-1 significantly reduced PRMT5 level in cells and mice xenografts model of cervical cancer...
May 1, 2018: Die Pharmazie
Sheng Huang, Yayun Chi, Yi Qin, Ziliang Wang, Bingqiu Xiu, Yonghui Su, Rong Guo, Liang Guo, Hefen Sun, Chujia Zeng, Shuling Zhou, Xin Hu, Sheng Liu, Zhimin Shao, Zhaohui Wu, Wei Jin, Jiong Wu
Macrophage-capping protein (CAPG) has been shown to promote cancer cell metastasis, although the mechanism remains poorly understood. Methods: Breast cancer (BC) tissue microarray was used to test the role of CAPG in the prognosis of BC patients. Xenograft mice model was used to validate the metastasis promotion role of CAPG in vivo. Gene expression array, chromatin immunoprecipitation and luciferase report assay were performed to search for the target genes of CAPG. Protein immunoprecipitation, MS/MS analysis, tissue microarray and histone methyltransferase assay were used to explore the mechanism of CAPG regulating stanniocalcin 1 (STC-1) transcription...
2018: Theranostics
Ishita Rehman, Suparna M Basu, Subhendu K Das, Sangheeta Bhattacharjee, Arijit Ghosh, Yves Pommier, Benu Brata Das
Human tyrosyl-DNA phosphodiesterases (TDP) hydrolyze the phosphodiester bond between DNA and the catalytic tyrosine of Top1 to excise topoisomerase I cleavage complexes (Top1cc) that are trapped by camptothecin (CPT) and by genotoxic DNA alterations. Here we show that the protein arginine methyltransferase PRMT5 enhances the repair of Top1cc by direct binding to TDP1 and arginine dimethylation of TDP1 at residues R361 and R586. Top1-induced replication-mediated DNA damage induces TDP1 arginine methylation, enhancing its 3'- phosphodiesterase activity...
April 30, 2018: Nucleic Acids Research
Keiichi Izumikawa, Hideaki Ishikawa, Richard J Simpson, Nobuhiro Takahashi
Chtop binds competitively to the arginine methyltransferases PRMT1 and PRMT5, thereby promoting the asymmetric or symmetric methylation of arginine residues, respectively. In cooperation with PRMT1, Chtop activates transcription of certain gene groups, such as the estrogen-inducible genes in breast cancer cells, the 5-hydroxymethylcytosine-modified genes involved in glioblastomagenesis, or the Zbp-89-dependent genes in erythroleukemia cells. Chtop also represses expression of the fetal γ-globin gene. In addition, Chtop is a component of the TREX complex that links transcription elongation to mRNA export...
April 23, 2018: RNA Biology
Pengyu Jing, Nan Zhao, Mingxiang Ye, Yong Zhang, Zhipei Zhang, Jianyong Sun, Zhengxin Wang, Jian Zhang, Zhongping Gu
Protein arginine methyltransferase 5 (PRMT5) functions as a tumor initiator to regulate several cancer progressions, such as proliferation and apoptosis, by catalyzing the symmetrical dimethylation (me2s) of arginine residues within targeted molecules. However, the exact role of PRMT5-mediated metastasis in lung cancer is not fully understood. Here, we illustrated its potential effects in lung cancer metastasis in vivo and vitro. PRMT5 was frequently overexpressed in lung tumors, and its expression was positively related to tumor stages, lymphatic metastasis and poor outcome...
April 18, 2018: Cancer Letters
Zhe Li, Jiwei Zhang, Xinyang Liu, Shengli Li, Qifeng Wang, Di Chen, Zhixiang Hu, Tao Yu, Jie Ding, Jinjun Li, Ming Yao, Jia Fan, Shenglin Huang, Qiang Gao, Yingjun Zhao, Xianghuo He
Recurrent chromosomal aberrations have led to the discovery of oncogenes or tumour suppressors involved in carcinogenesis. Here we characterized an oncogenic long intergenic non-coding RNA in the frequent DNA-gain regions in hepatocellular carcinoma (HCC), LINC01138 (long intergenic non-coding RNA located on 1q21.2). The LINC01138 locus is frequently amplified in HCC; the LINC01138 transcript is stabilized by insulin like growth factor-2 mRNA-binding proteins 1/3 (IGF2BP1/IGF2BP3) and is associated with the malignant features and poor outcomes of HCC patients...
April 20, 2018: Nature Communications
Fei Ye, Weiyao Zhang, Xiaoqing Ye, Jia Jin, Zhengbing Lv, Cheng Luo
Protein arginine methyltransferase 5 (PRMT5), a type II PRMT enzyme, is reported as an important therapeutic target in leukemia and lymphoma. In the present study, based on the combination of virtual screening and biochemical validations, we discovered a series of small-molecule inhibitors targeting PRMT5. Among those, DC_Y134 exhibited the most potent activity with IC50 value of 1.7 μM and displayed good selectivity against other methyltransferases. Further treatment with DC_Y134 inhibited the proliferation of several hematological malignancy cell lines by causing cell cycle arrest and apoptosis...
April 19, 2018: Journal of Chemical Information and Modeling
Kongkai Zhu, Chengshi Jiang, Hongrui Tao, Jingqiu Liu, Hua Zhang, Cheng Luo
As one of the most promising anticancer target in protein arginine methyltransferase (PRMT) family, PRMT5 has been drawing more and more attentions, and many efforts have been devoted to develop its inhibitors. In this study, three PRMT5 inhibitors (9, 16, and 23) with novel scaffolds were identified by performing pharmacophore- and docking-based virtual screening combined with in vitro radiometric-based scintillation proximity assay (SPA). Substructure search based on the scaffold of the most active 9 afforded 26 additional analogues, and SPA results indicated that two analogues (9-1 and 9-2) showed increased PRMT5 inhibitory activity compared with the parental compound...
March 30, 2018: Bioorganic & Medicinal Chemistry Letters
Yusuke Amano, Daisuke Matsubara, Taichiro Yoshimoto, Tomoko Tamura, Hiroshi Nishino, Yoshiyuki Mori, Toshiro Niki
Protein arginine methyltransferases (PRMT) 5, a member of type II arginine methyltransferases, catalyzes the symmetrical dimethylation of arginine residues on histone and non-histone substrates. Although the overexpression of PRMT5 has been reported in various cancers, its role in oral squamous cell carcinoma (OSCC) has not been elucidated. In the present study, we immunohistochemically examined the expression of PRMT5 in surgically resected oral epithelial dysplasia (OED, n = 8), oral intraepithelial neoplasia (OIN)/carcinoma in situ (CIS) (n = 11) and OSCC (n = 52) with or without contiguous OED lesions...
March 30, 2018: Pathology International
Norikazu Yabuta, Chie Ota, Towa Sasakura, Yoko Naito, Daisuke Okuzaki, Kohshiro Fukushima, Hiroshi Nojima
p63, a transcriptional factor that belongs to the p53 family, regulates epidermal differentiation, stemness, cell death, tumorigenesis, metastasis, and senescence. However, its molecular mechanism remains elusive. We report here that TAp63 phosphorylated at T46/T281 specifically upregulates the late cornified envelope 1C (LCE1C) gene that is essential at a relatively late stage of epithelial development. We identified these phosphorylation sites during a search for the targets of Cyclin G-associated kinase (GAK) in vitro...
March 20, 2018: Scientific Reports
Qianqian Wang, Jiahui Xu, Ying Li, Jumin Huang, Zebo Jiang, Yuwei Wang, Liang Liu, Elaine Lai Han Leung, Xiaojun Yao
Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM)-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors...
2018: Frontiers in Pharmacology
Ye-Fen Lu, Xue-Li Cai, Zheng-Zheng Li, Jing Lv, Yi-An Xiang, Jian-Jun Chen, Wei-Jing Chen, Wei-Yan Sun, Xiu-Mei Liu, Jian-Bo Chen
BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) have recently emerged as novel and potentially promising therapeutic targets in various cancers. However, the expression pattern and biological function of lncRNAs in glioma remain largely elusive. In the present study, we investigated the functional role of an lncRNA, small nucleolar RNA host gene 16 (SNHG16), in glioma. METHODS: The expression levels of SNHG16 and miR-4518 were measured using qRT-PCR. The relationship between the levels of SNHG16 and clinicopathologic features were statically analyzed...
2018: Cellular Physiology and Biochemistry
David E Timm, Valorie Bowman, Russell Madsen, Charles Rauch
Protein arginine methyl transferase 5 (PRMT5) is a signaling protein and histone modifying enzyme that is important in many cellular processes, including regulation of eukaryotic gene transcription. Reported here is a 3.7 Å structure of PRMT5, solved in complex with regulatory binding subunit MEP50 (methylosome associated protein 50, WDR77, p44), by single particle (SP) cryo-Electron Microscopy (cryo-EM) using micrographs of particles that are visibly crowded and aggregated. Despite suboptimal micrograph appearance, this cryo-EM structure is in good agreement with previously reported crystal structures of the complex, which revealed a 450 kDa hetero-octameric assembly having internal D2 symmetry...
2018: PloS One
Dariusz Zakrzewicz, Miroslava Didiasova, Marcus Krüger, Benedetto Daniele Giaimo, Tilman Borggrefe, Maren Mieth, Andreas C Hocke, Anna Zakrzewicz, Liliana Schaefer, Klaus T Preissner, Malgorzata Wygrecka
OBJECTIVES: Enolase-1-dependent cell surface proteolysis plays an important role in cell invasion. Although enolase-1 (Eno-1), a glycolytic enzyme, has been found on the surface of various cells, the mechanism responsible for its exteriorization remains elusive. Here, we investigated the involvement of post-translational modifications (PTMs) of Eno-1 in its lipopolysaccharide (LPS)-triggered trafficking to the cell surface. RESULTS: We found that stimulation of human lung adenocarcinoma cells with LPS triggered the monomethylation of arginine 50 (R50me) within Eno-1...
May 2018: Biochimica et Biophysica Acta
Emmanuel S Burgos, Ryan O Walters, Derek M Huffman, David Shechter
Methyltransferases use S -adenosyl-l-methionine (SAM) to deposit methyl marks. Many of these epigenetic 'writers' are associated with gene regulation. As cancer etiology is highly correlated with misregulated methylation patterns, methyltransferases are emerging therapeutic targets. Successful assignment of methyltransferases' roles within intricate biological networks relies on (1) the access to enzyme mechanistic insights and (2) the efficient screening of chemical probes against these targets. To characterize methyltransferases in vitro and in vivo , we report a highly-sensitive one-step deaminase-linked continuous assay where the S -adenosyl-l-homocysteine (SAH) enzyme-product is rapidly and quantitatively catabolized to S -inosyl-l-homocysteine (SIH)...
September 1, 2017: Chemical Science
Hai Jiang, Yue Zhu, Zhenyu Zhou, Junyang Xu, Shaowen Jin, Kang Xu, Heyun Zhang, Qing Sun, Jie Wang, Junyao Xu
Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, has roles in cell growth regulation and cancer development. However, the role of PRMT5 in hepatocellular carcinoma (HCC) progression remains unclear. Here, we showed that PRMT5 expression was frequently upregulated in HCC tissues, and its expression was inversely correlated with overall survival in HCC patients. PRMT5 knockdown markedly inhibited in vitro HCC proliferation and in vivo tumorigenesis. We revealed that the mechanism of PRMT5-induced proliferation was partially mediated by BTG downregulation, leading to cell cycle arrest during the G1 phase in HCC cells...
March 2018: Cancer Medicine
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