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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2019
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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. |
format | Online Article Text |
id | pubmed-6642535 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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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