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Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer

BACKGROUND: The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of this methyltransferase have been identified to date. METHODS: The clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. T...

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Autores principales: Hsu, Ming-Chuan, Tsai, Ya-Li, Lin, Chia-Hsien, Pan, Mei-Ren, Shan, Yan-Shen, Cheng, Tsung-Yen, Cheng, Skye Hung-Chun, Chen, Li-Tzong, Hung, Wen-Chun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642535/
https://www.ncbi.nlm.nih.gov/pubmed/31324208
http://dx.doi.org/10.1186/s13045-019-0769-7
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author Hsu, Ming-Chuan
Tsai, Ya-Li
Lin, Chia-Hsien
Pan, Mei-Ren
Shan, Yan-Shen
Cheng, Tsung-Yen
Cheng, Skye Hung-Chun
Chen, Li-Tzong
Hung, Wen-Chun
author_facet Hsu, Ming-Chuan
Tsai, Ya-Li
Lin, Chia-Hsien
Pan, Mei-Ren
Shan, Yan-Shen
Cheng, Tsung-Yen
Cheng, Skye Hung-Chun
Chen, Li-Tzong
Hung, Wen-Chun
author_sort Hsu, Ming-Chuan
collection PubMed
description BACKGROUND: The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of this methyltransferase have been identified to date. METHODS: The clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. The PRMT3 protein level of human pancreatic tumors was detected by immunoblotting and immunohistochemical staining. PRMT3-associated proteins and the methylation sites on the proteins were investigated using mass spectrometry. Seahorse Bioscience analyzed the metabolic reprogramming. Combination index analysis and xenograft animal model were conducted to explore the effects of combination of inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidative phosphorylation on tumor growth. RESULTS: We found that the expression of PRMT3 is upregulated in pancreatic cancer, and its expression is associated with poor survival. We identified GAPDH as a PRMT3-binding protein and demonstrated that GAPDH is methylated at R248 by PRMT3 in vivo. The methylation of GAPDH by PRMT3 enhanced its catalytic activity while the mutation of R248 abolished the effect. In cells, PRMT3 overexpression triggered metabolic reprogramming and enhanced glycolysis and mitochondrial respiration simultaneously in a GAPDH-dependent manner. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induced a synergistic inhibition on cellular growth in vitro and in vivo. CONCLUSION: Our results suggest that PRMT3 mediates metabolic reprogramming and cellular proliferation through methylating R248 of GAPDH, and double blockade of GAPDH and mitochondrial respiration could be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-019-0769-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-66425352019-07-29 Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer Hsu, Ming-Chuan Tsai, Ya-Li Lin, Chia-Hsien Pan, Mei-Ren Shan, Yan-Shen Cheng, Tsung-Yen Cheng, Skye Hung-Chun Chen, Li-Tzong Hung, Wen-Chun J Hematol Oncol Research BACKGROUND: The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of this methyltransferase have been identified to date. METHODS: The clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. The PRMT3 protein level of human pancreatic tumors was detected by immunoblotting and immunohistochemical staining. PRMT3-associated proteins and the methylation sites on the proteins were investigated using mass spectrometry. Seahorse Bioscience analyzed the metabolic reprogramming. Combination index analysis and xenograft animal model were conducted to explore the effects of combination of inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidative phosphorylation on tumor growth. RESULTS: We found that the expression of PRMT3 is upregulated in pancreatic cancer, and its expression is associated with poor survival. We identified GAPDH as a PRMT3-binding protein and demonstrated that GAPDH is methylated at R248 by PRMT3 in vivo. The methylation of GAPDH by PRMT3 enhanced its catalytic activity while the mutation of R248 abolished the effect. In cells, PRMT3 overexpression triggered metabolic reprogramming and enhanced glycolysis and mitochondrial respiration simultaneously in a GAPDH-dependent manner. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induced a synergistic inhibition on cellular growth in vitro and in vivo. CONCLUSION: Our results suggest that PRMT3 mediates metabolic reprogramming and cellular proliferation through methylating R248 of GAPDH, and double blockade of GAPDH and mitochondrial respiration could be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-019-0769-7) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-19 /pmc/articles/PMC6642535/ /pubmed/31324208 http://dx.doi.org/10.1186/s13045-019-0769-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Hsu, Ming-Chuan
Tsai, Ya-Li
Lin, Chia-Hsien
Pan, Mei-Ren
Shan, Yan-Shen
Cheng, Tsung-Yen
Cheng, Skye Hung-Chun
Chen, Li-Tzong
Hung, Wen-Chun
Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
title Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
title_full Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
title_fullStr Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
title_full_unstemmed Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
title_short Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
title_sort protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642535/
https://www.ncbi.nlm.nih.gov/pubmed/31324208
http://dx.doi.org/10.1186/s13045-019-0769-7
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