PRMT1 promotes neuroblastoma cell survival through ATF5

Zhong Yan Hua; Jeanne N. Hansen; Miao He; Shang Kun Dai; Yoonjung Choi; Melody D. Fulton; Sarah M. Lloyd; Marianna Szemes; Ji Sen; Han Fei Ding; James M. Angelastro; Xiang Fei; Hui Ping Li; Chao Ran Wu; Sheng Yong Yang; Karim Malik; Xiaomin Bao; Y. George Zheng; Chang Mei Liu; Nina F. Schor; Zhi Jie Li; Xing Guo Li

doi:10.1038/s41389-020-0237-9

PRMT1 promotes neuroblastoma cell survival through ATF5

Zhong Yan Hua, Jeanne N. Hansen, Miao He, Shang Kun Dai, Yoonjung Choi, Melody D. Fulton, Sarah M. Lloyd, Marianna Szemes, Ji Sen, Han Fei Ding, James M. Angelastro, Xiang Fei, Hui Ping Li, Chao Ran Wu, Sheng Yong Yang, Karim Malik, Xiaomin Bao, Y. George Zheng, Chang Mei Liu, Nina F. SchorZhi Jie Li, Xing Guo Li^*

^*Corresponding author for this work

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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.

Original language	English (US)
Article number	50
Journal	Oncogenesis
Volume	9
Issue number	5
DOIs	https://doi.org/10.1038/s41389-020-0237-9
State	Published - May 1 2020

Funding

thank Mary Georger (Dr. Laura Calvi’s lab at the University of Rochester) and Dr. Linda Callahan (the Confocal and Conventional Microscopy Core, University of Rochester) for technical assistance and equipment use with immunostaining. RNA-seq and transcriptome analyses were completed by the University of Rochester Genomics Research Center (URGRC). 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).

ASJC Scopus subject areas

Molecular Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hua, Z. Y., Hansen, J. N., He, M., Dai, S. K., Choi, Y., Fulton, M. D., Lloyd, S. M., Szemes, M., Sen, J., Ding, H. F., Angelastro, J. M., Fei, X., Li, H. P., Wu, C. R., Yang, S. Y., Malik, K., Bao, X., George Zheng, Y., Liu, C. M., ... Li, X. G. (2020). PRMT1 promotes neuroblastoma cell survival through ATF5. Oncogenesis, 9(5), Article 50. https://doi.org/10.1038/s41389-020-0237-9

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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.",

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AU - Fulton, Melody D.

AU - Lloyd, Sarah M.

AU - Szemes, Marianna

AU - Sen, Ji

AU - Ding, Han Fei

AU - Angelastro, James M.

AU - Fei, Xiang

AU - Li, Hui Ping

AU - Wu, Chao Ran

AU - Yang, Sheng Yong

AU - Malik, Karim

AU - Bao, Xiaomin

AU - George Zheng, Y.

AU - Liu, Chang Mei

AU - Schor, Nina F.

AU - Li, Zhi Jie

AU - Li, Xing Guo

PY - 2020/5/1

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N2 - 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.

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PRMT1 promotes neuroblastoma cell survival through ATF5

Abstract

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UN SDGs

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