1. PRMT1 promotes neuroblastoma cell survival through ATF5
- Author
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Shang Kun Dai, Marianna Szemes, Xiang Fei, Xingguo Li, Hui Ping Li, Han Fei Ding, Chao Ran Wu, Melody D. Fulton, Nina F. Schor, Xiaomin Bao, Zhi Jie Li, Y. George Zheng, Chang-Mei Liu, Jeanne N. Hansen, Sarah M. Lloyd, Ji Sen, Karim Malik, James M. Angelastro, Sheng Yong Yang, Miao He, Yoonjung Choi, and Zhong Yan Hua
- Subjects
0301 basic medicine ,Cancer Research ,Methyltransferase ,Pediatric Cancer ,Oncology and Carcinogenesis ,Activating transcription factor ,Biology ,lcsh:RC254-282 ,Article ,Paediatric cancer ,03 medical and health sciences ,Neuroblastoma ,0302 clinical medicine ,Rare Diseases ,medicine ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Molecular Biology ,Cancer ,Pediatric ,Effector ,Cell growth ,Neurosciences ,Oncogenes ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,In vitro ,030104 developmental biology ,Apoptosis ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Cancer research ,Biochemistry and Cell Biology ,Signal transduction ,Development of treatments and therapeutic interventions ,Biotechnology - Abstract
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.
- Published
- 2020