BACKGROUND: Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein SDHB, to which the cochaperone HSC20 binds. METHODS: In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations. RESULTS: We found that the SDHBR46Q mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4 ± 63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation.Furthermore, HIF1α, but not HIF2α, increased markedly and the cells showed a strong DNA CpG island methylatorphenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines. CONCLUSIONS: These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes.
BACKGROUND: Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein SDHB, to which the cochaperone HSC20 binds. METHODS: In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations. RESULTS: We found that the SDHBR46Q mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4 ± 63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation.Furthermore, HIF1α, but not HIF2α, increased markedly and the cells showed a strong DNA CpG island methylatorphenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines. CONCLUSIONS: These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes.
Authors: Katherine A Janeway; Su Young Kim; Maya Lodish; Vânia Nosé; Pierre Rustin; José Gaal; Patricia L M Dahia; Bernadette Liegl; Evan R Ball; Margarita Raygada; Angela H Lai; Lorna Kelly; Jason L Hornick; Maureen O'Sullivan; Ronald R de Krijger; Winand N M Dinjens; George D Demetri; Cristina R Antonescu; Jonathan A Fletcher; Lee Helman; Constantine A Stratakis Journal: Proc Natl Acad Sci U S A Date: 2010-12-20 Impact factor: 11.205
Authors: Ian P M Tomlinson; N Afrina Alam; Andrew J Rowan; Ella Barclay; Emma E M Jaeger; David Kelsell; Irene Leigh; Patricia Gorman; Hanan Lamlum; Shamima Rahman; Rebecca R Roylance; Simon Olpin; Stephen Bevan; Karen Barker; Nicholas Hearle; Richard S Houlston; Maija Kiuru; Rainer Lehtonen; Auli Karhu; Susa Vilkki; Päivi Laiho; Carita Eklund; Outi Vierimaa; Kristiina Aittomäki; Marja Hietala; Pertti Sistonen; Anders Paetau; Reijo Salovaara; Riitta Herva; Virpi Launonen; Lauri A Aaltonen Journal: Nat Genet Date: 2002-02-25 Impact factor: 38.330
Authors: Sakari Vanharanta; Mary Buchta; Sarah R McWhinney; Sanna K Virta; Mariola Peçzkowska; Carl D Morrison; Rainer Lehtonen; Andrzej Januszewicz; Heikki Järvinen; Matti Juhola; Jukka-Pekka Mecklin; Eero Pukkala; Riitta Herva; Maija Kiuru; Nina N Nupponen; Lauri A Aaltonen; Hartmut P H Neumann; Charis Eng Journal: Am J Hum Genet Date: 2003-12-18 Impact factor: 11.025
Authors: Youfeng Yang; Vladimir A Valera; Hesed M Padilla-Nash; Carole Sourbier; Cathy D Vocke; Manish A Vira; Mones S Abu-Asab; Gennady Bratslavsky; Maria Tsokos; Maria J Merino; Peter A Pinto; Ramaprasad Srinivasan; Thomas Ried; Len Neckers; W Marston Linehan Journal: Cancer Genet Cytogenet Date: 2010-01-01
Authors: Alberto Cascón; Lucía Inglada-Pérez; Iñaki Comino-Méndez; Aguirre A de Cubas; Rocío Letón; Jaume Mora; Mónica Marazuela; Juan Carlos Galofré; Miguel Quesada-Charneco; Mercedes Robledo Journal: Endocr Relat Cancer Date: 2013-05-30 Impact factor: 5.678
Authors: Christopher Ricketts; Emma R Woodward; Pip Killick; Mark R Morris; Dewi Astuti; Farida Latif; Eamonn R Maher Journal: J Natl Cancer Inst Date: 2008-08-26 Impact factor: 13.506
Authors: Esther Korpershoek; Bart-Jeroen Petri; Francien H van Nederveen; Winand N M Dinjens; Albert A Verhofstad; Wouter W de Herder; Sonja Schmid; Aurel Perren; Paul Komminoth; Ronald R de Krijger Journal: Endocr Relat Cancer Date: 2007-06 Impact factor: 5.678
Authors: Christopher J Ricketts; Brian Shuch; Cathy D Vocke; Adam R Metwalli; Gennady Bratslavsky; Lindsay Middelton; Youfeng Yang; Ming-Hui Wei; Stephen E Pautler; James Peterson; Catherine A Stolle; Berton Zbar; Maria J Merino; Laura S Schmidt; Peter A Pinto; Ramaprasad Srinivasan; Karel Pacak; W Marston Linehan Journal: J Urol Date: 2012-10-18 Impact factor: 7.450
Authors: Gregory P Holmes-Hampton; Daniel R Crooks; Ronald G Haller; Shuling Guo; Susan M Freier; Brett P Monia; Tracey A Rouault Journal: Hum Mol Genet Date: 2016-12-01 Impact factor: 6.150
Authors: Yang Liu; Ying Pang; Chunzhang Yang; Karel Pacak; Boqun Zhu; Ondrej Uher; Veronika Caisova; Thanh-Truc Huynh; David Taieb; Katerina Hadrava Vanova; Hans Kumar Ghayee; Jiri Neuzil; Mark Levine Journal: Clin Cancer Res Date: 2020-03-09 Impact factor: 12.531