Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors.

By Mengtao Xiao, Hui Yang, Wei Xu, Shenghong Ma, Huaipeng Lin, Honguang Zhu, Lixia Liu, Y. Liu, Chen Yang, Yanhui Xu and 4 more. Genes & Development, 2012

1,071 citations recorded by the source corpus.

Two Krebs cycle genes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are mutated in a subset of human cancers, leading to accumulation of their substrates, fumarate and succinate, respectively. Here we demonstrate that fumarate and succinate are competitive inhibitors of multiple α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases. Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively, which act as competitors of α-KG to broadly inhibit the activity of α-KG-dependent dioxygenases. In addition, ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC. Our study suggests that tumor-derived FH and SDH mutations accumulate fumarate and succinate, leading to enzymatic inhibition of multiple α-KG-dependent dioxygenases and consequent alterations of genome-wide histone and DNA methylation. These epigenetic alterations associated with mutations of FH and SDH likely contribute to tumorigenesis.

Subfields: Biochemistry, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0692bd51f83e69f21dab4f3e869a55299d72df6b

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Citations in the corpus

Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “Interestingly, recent evidence has further suggested that the accumulation of both succinate and fumarate that arise in SDH- and FH-deficient tumors respectively (as described above), may also inhibit various αKG-dependent dioxygenases, resulting in analogous deregulation of epigenetic modifications”
Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity (2016, background): “KDMs of the JmjC and JmjD family need a-ketoglutarate as a cofactor for the demethylation process (Lu et al., 2012), whereas metabolites with a similar molecular structure, such as fumarate, can act as antagonizing factors (Lu et al., 2012; Xiao et al., 2012), thereby inhibiting demethylation.”
Understanding the intersections between metabolism and cancer biology (2017, neutral): “Like D-2HG, these dicarboxylic acids interfere with dioxygenase function (Sciacovelli et al., 2016; Selak et al., 2005; Xiao et al., 2012).”
Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “The loss of succinate dehydrogenase or fumarate hydratase in tumors leads to altered ratios of α-ketoglutarate to succinate that can affect genome-wide methylation (6, 120, 121).”
SDH mutations establish a hypermethylator phenotype in paraganglioma. (2013, background): “Fumarate, like succinate, is a competitive inhibitor of 2-OG-dependent dioxygenases (Xiao et al., 2012), so these findings strongly suggest that FH inactivation causes PGL/PCC by establishing a hypermethylator phenotype.”
Influence of Metabolism on Epigenetics and Disease (2013, neutral): “R-2HG, succinate, and fumarate are all capable of inhibiting multiple 2-oxoglutarate-dependent dioxygenases, including the JmjC histone demethylases and TET proteins, when present at sufficiently high concentrations (Figure 6B) (Cervera et al., 2009; Chowdhury et al., 2011; Figueroa et al., 2010; Ko”
Epigenetic Determinants of Cancer. (2016, background): “Interestingly, other Krebs cycle control genes, when mutated in certain tumor types, can also result in decreased a-ketoglutarate levels and similar chromatin and DNA methylation abnormalities (Xiao et al. 2012; Mason and Hornick 2013).”
Repurposing mitochondria from ATP production to ROS generation drives a pro-inflammatory phenotype in macrophages that depends on succinate oxidation by complex II (2016, background): “TNF-a production, or this may be a result of epigenetic alterations of the TNF-a gene, which have been reported elsewhere (Sullivan et al., 2007; Xiao et al., 2012).”
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, neutral): “Similarly, inactivation mutations in SDH and FH, which have been identified in a subset of cancers, lead tomarked accumulation of succinate and fumarate, both of which can inhibit a-KG-dependent dioxygenases (Xiao et al., 2012).”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “These epigenetic alterations induced by FH or SDH loss contribute to tumorigenesis (Xiao et al., 2012).”
Targeting Metabolism for Cancer Therapy (2017, background): “Familial cancer syndromes caused by fumarate hydratase (FH) or succinate dehydrogenase (SDH) deletion suggest that these TCA enzymes can behave as classical tumor suppressors.”