Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells

Emanuel Gonçalves,Marco Sciacovelli,Ana S.H Costa,Maxine Gia Binh Tran,Timothy Isaac Johnson,Daniel Machado,Christian Frezza,Julio Saez-Rodriguez

doi:10.1016/j.ymben.2017.11.011

Abstract

Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications.

Highlights

Cancer is thought to arise from an abnormal accumulation of somatic mutations in the genome that drive complex and profound alterations of the cellular phenotype (Stratton et al, 2009)
Several studies have shown that signalling has a broad importance in regulating the activity of metabolic enzymes involved in central carbon metabolism and other peripheral pathways (Gonçalves et al, 2017; Oliveira et al, 2015; Raguz Nakic et al, 2016)
Proteomics experiment covered a total of 1468 unique proteins (Supplementary Table 1) and, in agreement with fumarate hydratase (FH) mutation, FH was underexpressed in UOK262 cell lines

Summary

Introduction

Cancer is thought to arise from an abnormal accumulation of somatic mutations in the genome that drive complex and profound alterations of the cellular phenotype (Stratton et al, 2009). FH mutations lead to the impairment of the catalytic activity of the enzyme and thereby to the accumulation of its substrate, fumarate, and to profound metabolic changes that we and others have extensively characterised (Isaacs et al, 2005; Sciacovelli et al, 2016; Tomlinson et al, 2002). How these metabolic changes are orchestrated by signalling processes has not been investigated

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Conclusion