EPZ015666, a selective protein arginine methyltransferase 5 (PRMT5) inhibitor with an antitumour effect in retinoblastoma

Xing Liu; JianZhong He; Longbing Mao; Yanyan Zhang; WenWen Cui; Sujuan Duan; Alan Jiang; Yang Gao; Yi Sang; Guofu Huang

doi:10.1016/j.exer.2020.108286

EPZ015666, a selective protein arginine methyltransferase 5 (PRMT5) inhibitor with an antitumour effect in retinoblastoma

Exp Eye Res. 2021 Jan:202:108286. doi: 10.1016/j.exer.2020.108286. Epub 2020 Oct 6.

Authors

Xing Liu¹, JianZhong He², Longbing Mao¹, Yanyan Zhang¹, WenWen Cui¹, Sujuan Duan¹, Alan Jiang³, Yang Gao¹, Yi Sang³, Guofu Huang⁴

Affiliations

¹ Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, 128 Xiangshan Northern Road, Nanchang City, 330008 Jiangxi Province, People's Republic of China.
² Department of Ophthalmology, The People's Hospital of Pingxiang City, Pingxiang City, 337055, Jiangxi Province, People's Republic of China.
³ Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, The Third Affiliated Hospital of Nanchang University, 128 Xiangshan Northern Road, Nanchang City, 330008, Jiangxi Province, People's Republic of China.
⁴ Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, 128 Xiangshan Northern Road, Nanchang City, 330008 Jiangxi Province, People's Republic of China; Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, The Third Affiliated Hospital of Nanchang University, 128 Xiangshan Northern Road, Nanchang City, 330008, Jiangxi Province, People's Republic of China. Electronic address: hgf2222@sina.com.

PMID: 33035554
DOI: 10.1016/j.exer.2020.108286

Abstract

Retinoblastoma (RB) is the most common intraocular malignant tumour in infants, and chemotherapy has been the primary therapy method in recent years. PRMT5 is an important member of the protein arginine methyltransferase family, which plays an important role in various tumours. Our study showed that PRMT5 was overexpressed in retinoblastoma and played an important role in retinoblastoma cell growth. EPZ015666 is a novel PRMT5 inhibitor, and we found that it inhibited retinoblastoma cell proliferation and led to cell cycle arrest at the G1 phase. At the same time, EPZ015666 regulated cell cycle related protein (P53, P21, P27, CDK2) expression. In brief, our study showed that PRMT5 promoted retinoblastoma growth, the PRMT5 inhibitor EPZ015666 inhibited retinoblastoma in vitro by regulating P53-P21/P27-CDK2 signaling pathways and slowed retinoblastoma growth in a xenograft model.

Keywords: EPZ015666; PRMT5; Retinoblastoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / therapeutic use*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors / therapeutic use*
Humans
Immunohistochemistry
Isoquinolines / therapeutic use*
Male
Mice
Mice, Nude
Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
Protein-Arginine N-Methyltransferases / metabolism
Pyrimidines / therapeutic use*
Real-Time Polymerase Chain Reaction
Retinal Neoplasms / drug therapy*
Retinal Neoplasms / enzymology
Retinal Neoplasms / pathology
Retinoblastoma / drug therapy*
Retinoblastoma / enzymology
Retinoblastoma / pathology
Tetrazolium Salts
Thiazoles
Time Factors
Transplantation, Heterologous

Substances

Antineoplastic Agents
Enzyme Inhibitors
GSK3235025
Isoquinolines
Pyrimidines
Tetrazolium Salts
Thiazoles
Prmt5 protein, mouse
Protein-Arginine N-Methyltransferases
thiazolyl blue