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

Animals Cell Line, Tumor Cellular Reprogramming Techniques / methods Humans Mice Pancreatic Neoplasms / genetics Protein-Arginine N-Methyltransferases / metabolism
Glyceraldehyde-3-phosphate dehydrogenase Metabolic reprogramming Methylation Protein arginine methyltransferase 3

Journal

Journal of hematology & oncology
ISSN: 1756-8722
Titre abrégé: J Hematol Oncol
Pays: England
ID NLM: 101468937

Informations de publication

Date de publication:
19 07 2019
Historique:
received: 08 04 2019
accepted: 08 07 2019
entrez: 21 7 2019
pubmed: 22 7 2019
medline: 1 8 2020
Statut: epublish

Résumé

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. 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1186/s13045-019-0769-7 PMID: 31324208 PMC: PMC6642535
pubmed: 31324208
doi: 10.1186/s13045-019-0769-7
pii: 10.1186/s13045-019-0769-7
pmc: PMC6642535
doi:

Substances chimiques

Protein-Arginine N-Methyltransferases EC 2.1.1.319

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

79

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Auteurs

Ming-Chuan Hsu (MC)

National Institute of Cancer Research, National Health Research Institutes, No. 367, Shengli Road, Tainan, 704, Taiwan.

Ya-Li Tsai (YL)

National Institute of Cancer Research, National Health Research Institutes, No. 367, Shengli Road, Tainan, 704, Taiwan.

Chia-Hsien Lin (CH)

National Institute of Cancer Research, National Health Research Institutes, No. 367, Shengli Road, Tainan, 704, Taiwan.

Mei-Ren Pan (MR)

Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.

Yan-Shen Shan (YS)

Institute of Clinical Medicine, National Cheng Kung University, Tainan, 704, Taiwan.
Department of Surgery, National Cheng Kung University Hospital, Tainan, 704, Taiwan.

Tsung-Yen Cheng (TY)

Department of Surgery, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, 112, Taiwan.

Skye Hung-Chun Cheng (SH)

Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, 112, Taiwan.

Li-Tzong Chen (LT)

National Institute of Cancer Research, National Health Research Institutes, No. 367, Shengli Road, Tainan, 704, Taiwan.
Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, 704, Taiwan.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.

Wen-Chun Hung (WC)

National Institute of Cancer Research, National Health Research Institutes, No. 367, Shengli Road, Tainan, 704, Taiwan. hung1228@nhri.org.tw.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. hung1228@nhri.org.tw.

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Classifications MeSH

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Recherchemedicale.com › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Protein arginine methyltransferase 3-induced...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Protein Methyltransferases › Protein-arginine N-methyltransferases › Protein arginine methyltransferase 3-induced...