机构：[1]Department of Pediatrics, University of Rochester School of Medicine andDentistry, Rochester, NY, USA[2]Liaoning Key Laboratory of Research andApplication of Animal Models for Environmental and Metabolic Diseases,Medical Research Center, Shengjing Hospital of China Medical University,Shenyang, China中国医科大学附属盛京医院[3]Laboratory of Anesthesia and Critical Care Medicine,Department of Anesthesiology, Translational Neuroscience Center, West ChinaHospital, Sichuan University, Chengdu, China[4]State Key Laboratory of StemCell and Reproductive Biology, Institute of Zoology, Chinese Academy ofSciences, Beijing, China[5]Department of Pharmaceutical and BiochemicalSciences, College of Pharmacy, University of Georgia, Athens, GA, USA[6]Departments of Molecular Biosciences and Dermatology, NorthwesternUniversity, Evanston, IL, USA[7]Cancer Epigenetics Laboratory, School of Cellularand Molecular Medicine, University of Bristol, Bristol, UK[8]State Key Laboratoryof Biotherapy/Collaborative Innovation Center for Biotherapy, West ChinaHospital, West China Medical School, Sichuan University, Chengdu, China四川大学华西医院[9]TheGeorgia Cancer Center, Augusta University, Augusta, GA, USA[10]Department ofMolecular Biosciences, University of California, Davis School of VeterinaryMedicine, Davis, CA, USA[11]Shengjing Hospital of China Medical University,Shenyang, China中国医科大学附属盛京医院[12]Department of Pulmonary and Critical Care Medicine,Shenzhen Renmin Hospital, Shenzhen, China深圳市康宁医院深圳市人民医院深圳医学信息中心[13]Department of Anesthesiology,Shenzhen Renmin Hospital, Shenzhen, China深圳市康宁医院深圳市人民医院深圳医学信息中心[14]Wilmot Cancer Institute,University of Rochester School of Medicine and Dentistry, Rochester, NY, USA[15]Present address: Department of Biology, Colgate University, Hamilton, NY,USA[16]Present address: National Institute of Neurological Disorders & Stroke,National Institutes of Health, Bethesda, MD, USA
Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.
基金：
This work was supported by
the Andrew McDonough B+ (Be Positive) Foundation’s Childhood Cancer
Research Award (X.-G.L.), the Children’s Cancer Research Fund’s Emerging
Scientist Award (X.-G.L.), the Strong Children’s Research Center Small Grants
Program (X.-G.L.), the Crosby’s Fund for Neuroblastoma Pediatric Cancer
Research (N.F.S. and X.-G.L.), and a NIH Grant R01GM126154 (Y.G.Z.). X.-G.L. is an
Infinite Love for Kids Fighting Cancer Independent Investigator and Bear
Necessities Pediatric Cancer Foundation Independent Investigator (No:
19IN31).
第一作者机构：[1]Department of Pediatrics, University of Rochester School of Medicine andDentistry, Rochester, NY, USA[2]Liaoning Key Laboratory of Research andApplication of Animal Models for Environmental and Metabolic Diseases,Medical Research Center, Shengjing Hospital of China Medical University,Shenyang, China
通讯作者：
通讯机构：[1]Department of Pediatrics, University of Rochester School of Medicine andDentistry, Rochester, NY, USA[14]Wilmot Cancer Institute,University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
推荐引用方式(GB/T 7714)：
Zhong-Yan Hua,Jeanne N. Hansen,Miao He,et al.PRMT1 promotes neuroblastoma cell survival through ATF5[J].ONCOGENESIS.2020,9(5):doi:10.1038/s41389-020-0237-9.
APA：
Zhong-Yan Hua,Jeanne N. Hansen,Miao He,Shang-Kun Dai,Yoonjung Choi...&Xing-Guo Li.(2020).PRMT1 promotes neuroblastoma cell survival through ATF5.ONCOGENESIS,9,(5)
MLA：
Zhong-Yan Hua,et al."PRMT1 promotes neuroblastoma cell survival through ATF5".ONCOGENESIS 9..5(2020)
