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Metabolites 2014, 4(3), 640-654;

The Succinated Proteome of FH-Mutant Tumours

Cancer Biology and Metabolism Group, Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK
Central Proteomics Facility, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK
Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LJ, UK
Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, #12-01,117599, Singapore
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 16 May 2014 / Revised: 21 July 2014 / Accepted: 24 July 2014 / Published: 7 August 2014
(This article belongs to the Special Issue Cancer Metabolomics)
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Inherited mutations in the Krebs cycle enzyme fumarate hydratase (FH) predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity in HLRCC tumours causes accumulation of the Krebs cycle intermediate fumarate to high levels, which may act as an oncometabolite through various, but not necessarily mutually exclusive, mechanisms. One such mechanism, succination, is an irreversible non-enzymatic modification of cysteine residues by fumarate, to form S-(2-succino)cysteine (2SC). Previous studies have demonstrated that succination of proteins including glyceraldehyde 3-phosphate dehydrogenase (GAPDH), kelch-like ECH-associated protein 1 (KEAP1) and mitochondrial aconitase (ACO2) can have profound effects on cellular metabolism. Furthermore, immunostaining for 2SC is a sensitive and specific biomarker for HLRCC tumours. Here, we performed a proteomic screen on an FH-mutant tumour and two HLRCC-derived cancer cell lines and identified 60 proteins where one or more cysteine residues were succinated; 10 of which were succinated at cysteine residues either predicted, or experimentally proven, to be functionally significant. Bioinformatic enrichment analyses identified most succinated targets to be involved in redox signaling. To our knowledge, this is the first proteomic-based succination screen performed in human tumours and cancer-derived cells and has identified novel 2SC targets that may be relevant to the pathogenesis of HLRCC. View Full-Text
Keywords: fumarate hydratase; succination; cysteine; renal cancer; hereditary leiomyomatosis and renal cell cancer (HLRCC); oncometabolite; biomarker; reactive oxygen species (ROS) fumarate hydratase; succination; cysteine; renal cancer; hereditary leiomyomatosis and renal cell cancer (HLRCC); oncometabolite; biomarker; reactive oxygen species (ROS)

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Yang, M.; Ternette, N.; Su, H.; Dabiri, R.; Kessler, B.M.; Adam, J.; Teh, B.T.; Pollard, P.J. The Succinated Proteome of FH-Mutant Tumours. Metabolites 2014, 4, 640-654.

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