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Open Access 01-12-2019 | Pancreatic Cancer | Research

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

Authors: Ming-Chuan Hsu, Ya-Li Tsai, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Skye Hung-Chun Cheng, Li-Tzong Chen, Wen-Chun Hung

Published in: Journal of Hematology & Oncology | Issue 1/2019

Abstract

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.

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Title: Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
Authors: Ming-Chuan Hsu
Ya-Li Tsai
Chia-Hsien Lin
Mei-Ren Pan
Yan-Shen Shan
Tsung-Yen Cheng
Skye Hung-Chun Cheng
Li-Tzong Chen
Wen-Chun Hung
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Pancreatic Cancer
Pancreatic Cancer
Published in: Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-019-0769-7

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Abstract

Background

Methods

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