Targeting protein arginine methyltransferase 5 inhibits human hepatocellular carcinoma growth via the downregulation of beta-catenin.

Autor: Zhang B; 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., Dong S; 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., Li Z; Gansu Provincial Second People's Hospital, Lanzhou, 730000, China. lizhongxin03@sina.com., Lu L; 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., Zhang S; 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., Chen X; 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., Cen X; 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., Wu Y; 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.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2015 Nov 05; Vol. 13, pp. 349. Date of Electronic Publication: 2015 Nov 05.
DOI: 10.1186/s12967-015-0721-8
Abstrakt: 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.
Databáze: MEDLINE
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