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Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4 alpha

文献类型：期刊论文

作者Zheng, Bai-Nan4; Ding, Chen-Hong4; Chen, Shi-Jie5; Zhu, Kongkai6; Shao, Jingwei5; Feng, Jifeng4; Xu, Wen-Ping4; Cai, Ling-Yan1; Zhu, Chang-Peng4; Duan, Wenhu5
刊名THERANOSTICS
出版日期2019
卷号9期号:9页码:2606-2617
关键词PRMT5 HNF4 alpha hepatocellular carcinoma cancer stem cells
ISSN号1838-7640
DOI10.7150/thno.32344
通讯作者Zhang, Xin(zhang68@hotmail.com) ; Luo, Cheng(cluo@simm.ac.cn) ; Xie, Wei-Fen(weifenxie@medmail.com.cn)
英文摘要Background: Liver cancer stem cells (LCSCs) are responsible for the initiation, progression and chemoresistance of liver cancer. However, no agent targeting LCSC is available in the clinic to date. Here, we investigated the effects of targeting protein arginine methyltransferase 5 (PRMT5), an epigenetic regulator, on LCSCs and HCC using a novel PRMT5 inhibitor DW14800. Methods: Tumor spheroid formation culture was used to enrich LCSCs and assess their self-renewal capability. Human alpha-1-antitrypsin (A1AT) ELISA, acetylated low-density lipoprotein (ac-LDL) uptake, periodic acid-Schiff (PAS) reactions and senescence associated P-galactosidase (SA-beta-gal) activity assays were performed to examine the differentiation status of HCC cells. The effects of DW14800 on HCC malignancy were assessed in HCC cell lines and on an HCC xenograft model in mice. Chromatin immunoprecipitation was applied to clarify the transcriptional regulation of HNF4 alpha by PRMT5-mediated Histone H4 arginine-3 symmetrical dimethylation (H4R3me2s). Results: Quantitative real-time PCR revealed that the expression of PRMT5 was upregulated in LCSCs. DW14800 specifically decreased the symmetrical dimethylation of arginine residues in HCC cells. Treatment of DW14800 suppressed the self-renewal capacity of LCSCs while re-establishing hepatocyte-specific characteristics in HCC cells. DW14800 displayed antitumor effects in HCC cells in vitro and in xenograft HCC in vivo. Importantly, ChlP assay showed that PRMT5 and H4R3me2s bound to the promoter region of HNF4 alpha gene, and DW14800 increased the expression of HNF4 alpha via reducing the H4R3me2s levels and enhancing the transcription of HNF4 alpha. Conclusions: Our data revealed the significance of targeting PRMT5 activity in LCSC elimination and HCC differentiation, and proposed that DW14800 may represent a promising therapeutic agent for HCC in the clinic.
WOS关键词ARGININE METHYLTRANSFERASE 5 ; SELECTIVE INHIBITOR ; METHYLATION ; PROTEIN ; POTENT
资助项目National Natural Science Foundation of China[81530019] ; National Natural Science Foundation of China[81572377] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[81772523] ; National Natural Science Foundation of China[81703415] ; National Natural Science Foundation of China[81803438] ; Shanghai Science and Technology Committee[15431907100] ; National Science and Technology Major Project[2018ZX09711002] ; K.C. Wong Education Foundation ; Shanghai Sailing Program[17YF1423100]
WOS研究方向Research & Experimental Medicine
语种英语
WOS记录号WOS:000465285400012
出版者IVYSPRING INT PUBL
源URL[http://119.78.100.183/handle/2S10ELR8/290011]  
专题新药研究国家重点实验室
通讯作者Zhang, Xin; Luo, Cheng; Xie, Wei-Fen
作者单位1.Tongji Univ, Shanghai East Hosp, Dept Gastroenterol, Shanghai 200120, Peoples R China
2.Pilot Natl Lab Marine Sci & Technol, Open Studio Druggabil Res Marine Nat Prod, Qingdao 266237, Shandong, Peoples R China
3.Second Mil Med Univ, Changzheng Hosp, Dept Pharm, 415 Fengyang Rd, Shanghai 200003, Peoples R China
4.Second Mil Med Univ, Changzheng Hosp, Dept Gastroenterol, 415 Fengyang Rd, Shanghai 200003, Peoples R China
5.Chinese Acad Sci, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China
7.Second Mil Med Univ, Int Cooperat Lab Signal Transduct Eastern Hepatob, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zheng, Bai-Nan,Ding, Chen-Hong,Chen, Shi-Jie,et al. Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4 alpha[J]. THERANOSTICS,2019,9(9):2606-2617.
APA Zheng, Bai-Nan.,Ding, Chen-Hong.,Chen, Shi-Jie.,Zhu, Kongkai.,Shao, Jingwei.,...&Xie, Wei-Fen.(2019).Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4 alpha.THERANOSTICS,9(9),2606-2617.
MLA Zheng, Bai-Nan,et al."Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4 alpha".THERANOSTICS 9.9(2019):2606-2617.

入库方式： OAI收割

来源：上海药物研究所

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