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Theranostics 2019; 9(9):2606-2617. doi:10.7150/thno.32344 This issue Cite

Research Paper

Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4α

Bai-Nan Zheng1,*, Chen-Hong Ding1,*, Shi-Jie Chen2,*, Kongkai Zhu3, Jingwei Shao2, Jifeng Feng1, Wen-Ping Xu1, Ling-Yan Cai4, Chang-Peng Zhu1, Wenhu Duan2, Jin Ding5, Xin Zhang1,6✉, Cheng Luo2,7✉, Wei-Fen Xie1,4✉

1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
2. Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China
3. School of Biological Science and Technology, University of Jinan, Jinan 250022, China
4. Departments of Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, 200120, China
5. International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
6. Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
7. Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, China
*These authors contributed equally

✉ Corresponding authors: Wei-Fen Xie, Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Tel.: (86-21) 8188-5341; Fax: (86-21) 8188-9624; E-mail: weifenxiecom.cn More

Citation:
Zheng BN, Ding CH, Chen SJ, Zhu K, Shao J, Feng J, Xu WP, Cai LY, Zhu CP, Duan W, Ding J, Zhang X, Luo C, Xie WF. Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4α. Theranostics 2019; 9(9):2606-2617. doi:10.7150/thno.32344. https://www.thno.org/v09p2606.htm
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Abstract

Graphic abstract

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 β-galactosidase (SA-β-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 HNF4α 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, ChIP assay showed that PRMT5 and H4R3me2s bound to the promoter region of HNF4α gene, and DW14800 increased the expression of HNF4α via reducing the H4R3me2s levels and enhancing the transcription of HNF4α.

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.

Keywords: PRMT5, HNF4α, hepatocellular carcinoma, cancer stem cells

Citation styles

APA
Zheng, B.N., Ding, C.H., Chen, S.J., Zhu, K., Shao, J., Feng, J., Xu, W.P., Cai, L.Y., Zhu, C.P., Duan, W., Ding, J., Zhang, X., Luo, C., Xie, W.F. (2019). Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4α. Theranostics, 9(9), 2606-2617. https://doi.org/10.7150/thno.32344.

ACS
Zheng, B.N.; Ding, C.H.; Chen, S.J.; Zhu, K.; Shao, J.; Feng, J.; Xu, W.P.; Cai, L.Y.; Zhu, C.P.; Duan, W.; Ding, J.; Zhang, X.; Luo, C.; Xie, W.F. Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4α. Theranostics 2019, 9 (9), 2606-2617. DOI: 10.7150/thno.32344.

NLM
Zheng BN, Ding CH, Chen SJ, Zhu K, Shao J, Feng J, Xu WP, Cai LY, Zhu CP, Duan W, Ding J, Zhang X, Luo C, Xie WF. Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4α. Theranostics 2019; 9(9):2606-2617. doi:10.7150/thno.32344. https://www.thno.org/v09p2606.htm

CSE
Zheng BN, Ding CH, Chen SJ, Zhu K, Shao J, Feng J, Xu WP, Cai LY, Zhu CP, Duan W, Ding J, Zhang X, Luo C, Xie WF. 2019. Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4α. Theranostics. 9(9):2606-2617.

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