Cisplatin inhibits SIRT3-deacetylation MTHFD2 to disturb cellular redox balance in colorectal cancer cell

Xingyou Wan,Qian Qi,Chen-Ying Liu,Xinyuan Chen,Dejian Zhou,Peng Du,Sheng Xiang,Eyal Arbely,Chao Wang,Zhenyu Huang,Wei Yu

doi:10.1038/s41419-020-02825-y

Abstract

The folate-coupled metabolic enzyme MTHFD2 (the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase) confers redox homeostasis and drives cancer cell proliferation and migration. Here, we show that MTHFD2 is hyperacetylated and lysine 88 is the critical acetylated site. SIRT3, the major deacetylase in mitochondria, is responsible for MTHFD2 deacetylation. Interestingly, chemotherapeutic agent cisplatin inhibits expression of SIRT3 to induce acetylation of MTHFD2 in colorectal cancer cells. Cisplatin-induced acetylated K88 MTHFD2 is sufficient to inhibit its enzymatic activity and downregulate NADPH levels in colorectal cancer cells. Ac-K88-MTHFD2 is significantly decreased in human colorectal cancer samples and is inversely correlated with the upregulated expression of SIRT3. Our findings reveal an unknown regulation axis of cisplatin-SIRT3-MTHFD2 in redox homeostasis and suggest a potential therapeutic strategy for cancer treatments by targeting MTHFD2.

Highlights

IntroductionKnown as one-carbon (1C) metabolism, supplies a one-carbon group that is transferred to biomolecules, such as amino acids and nucleotides
Folate metabolism, known as one-carbon (1C) metabolism, supplies a one-carbon group that is transferred to biomolecules, such as amino acids and nucleotides
To confirm that MTHFD2 is acetylated in cells, we first overexpressed full-length human MTHFD2 in HEK293T cells following treating with nicotinamide (NAM), a common deacetylase inhibitor against the Sirtuin family[16]

Summary

Introduction

Known as one-carbon (1C) metabolism, supplies a one-carbon group that is transferred to biomolecules, such as amino acids and nucleotides. These metabolites are required for nucleotide synthesis and methylation reactions[1]. Recent studies have shown that the mitochondrial one-carbon pathway is often reprogrammed in cancer cells[2]. MTHFD2 performs two main reactions in the one-carbon metabolism: the 5,10methylene-THF (CH2-THF) dehydrogenase and 5,10methenyl-THF (CH+-THF) cyclohydrolase. The generation of NADPH by MTHFD2 is able to overcome oxidative stress and maintain redox homeostasis, which are critical steps for tumor progression[3].

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Conclusion