title: Targeting protein arginine methyltransferase 5 inhibits human hepatocellular carcinoma growth via the downregulation of beta-catenin.
abstract: BACKGROUND
  Protein arginine methyltransferase 5 (PRMT5), a type II PRMT, is highly expressed in some tumors, but its role in hepatocellular carcinoma (HCC) is still unknown.
  
  
  METHODS
  PRMT5 level in HCC specimens was determined by immunohistochemical staining and the association with clinicopathologic features was evaluated. PRMT5 was inhibited by AMI-1 (a small molecule inhibitor of PRMTs) or small interference RNA (siRNA). The proliferation of HCC cells was tested by Cell Counting Kit-8, cell migration was evaluated by Transwell assay and cell cycle and apoptosis were analyzed by flow cytometry. The effect of AMI-1 on HCC in vivo was examined by mouse xenograft model.
  
  
  RESULTS
  PRMT5 expression was markedly upregulated in HCC tissues, and correlated inversely with overall patient survival. Knockdown of PRMT5 significantly reduced the proliferation of HCC cells, but did not affect the growth of normal liver cells. Furthermore, β-catenin was identified as a target of PRMT5. Silencing PRMT5 significantly down-regulated the expression of β-catenin and the downstream effector Cyclin D1 in HCC cells. AMI-1 strongly inhibited HCC growth in vivo, increased the ratio of Bax/Bcl-2, and led to apoptosis and loss of migratory activity in several HCC cells. Meanwhile, AMI-1 decreased the expression levels of symmetric dimethylation of H4 (H4R3me2s), a histone mark of PRMT5.
  
  
  CONCLUSIONS
  PRMT5 plays an important role in HCC. PRMT5 may be a promising target for HCC therapy.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University; Key Lab of Preclinical Study for New Drugs of Gansu Province, No 199, Dongang West Road, Lanzhou, 730000, Gansu, China. zhangbl@lzu.edu.cn.
authors.forename: Baolai
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University; Key Lab of Preclinical Study for New Drugs of Gansu Province, No 199, Dongang West Road, Lanzhou, 730000, Gansu, China. dongshh@lzu.edu.cn.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Dong
authors.affiliation: Gansu Provincial Second People's Hospital, Lanzhou, 730000, China. lizhongxin03@sina.com.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University; Key Lab of Preclinical Study for New Drugs of Gansu Province, No 199, Dongang West Road, Lanzhou, 730000, Gansu, China. lulill@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University; Key Lab of Preclinical Study for New Drugs of Gansu Province, No 199, Dongang West Road, Lanzhou, 730000, Gansu, China. zhangsu701@163.com.
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University; Key Lab of Preclinical Study for New Drugs of Gansu Province, No 199, Dongang West Road, Lanzhou, 730000, Gansu, China. 18093747791@163.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China. john_chinese@tom.com.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cen
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University; Key Lab of Preclinical Study for New Drugs of Gansu Province, No 199, Dongang West Road, Lanzhou, 730000, Gansu, China. wuyj@lzu.edu.cn.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009282:Naphthalenesulfonates / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C535077:7,7'-carbonylbis(azanediyl) bis(4-hydroxynaphthalene-2-sulfonic acid; C495270:CTNNB1 protein, human; D009282:Naphthalenesulfonates; D034741:RNA, Small Interfering; D051176:beta Catenin; D014508:Urea; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases