D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

An, Lin; Abbas, Saman; Kim, Sang Woo; Ortega, Manoela Marques; Bouamar, Hakim; Escobedo, Yissela; Varadarajan, Prakash; Qin, Yuejuan; Sudderth, Jessica; Schulz, E.; Deutsch, Alexander; Mohan, Sumitra; Ulz, Peter; Neumeister, Peter; Rakheja, Dinesh; Gao, Xiaoli; Hinck, Andrew P.; Weintraub, Susan E; DeBerardinis, Ralph J.; Sill, Heinz; Dahia, Patricia L.M.; Aguiar, Ricardo C.T.

doi:10.1038/ncomms8768

Cited by 65 publications

(76 citation statements)

References 46 publications

(70 reference statements)

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“…As Tet enzymatic activity can be altered by availability of the co‐substrate α‐KG, the level of this metabolite was monitored in heart and resulted significantly reduced after HFD feeding ( Figure A). Hence, we tested whether α‐KG decrease was attributable to defects in mitochondria, which are the primary organelles deputed to fatty acid oxidation and in which α‐KG synthesis largely occurs .…”

Section: Resultsmentioning

confidence: 99%

High Dietary Fat Intake Affects DNA Methylation/Hydroxymethylation in Mouse Heart: Epigenetic Hints for Obesity‐Related Cardiac Dysfunction

Ciccarone

Castelli

Ioannilli

et al. 2018

Molecular Nutrition Food Res

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Scope Epigenetic aberrations caused by environmental factors and lifestyle choices have been associated with the development of a number of pathologies, including cardiovascular disorders. However, whether obesity‐related heart dysfunction can occur via epigenetic mechanisms is largely undisclosed. The manifested role of DNA hydroxymethylation in heart pathophysiology prompts an investigation of its levels/machinery in heart of mice fed with high‐fat diet (HFD) and its possible relation with genes linked to obesity‐associated cardiac remodeling. Methods and results Alterations in levels of DNA methylation/hydroxymethylation modifications and in expression of Tet family of DNA hydroxylases are observed in hearts of mice treated with HFD for 8 and 16 weeks. Decreased levels of the Tet co‐substrate α‐ketoglutarate are also observed and associate with mitochondrial mass reduction and augmented oxidative stress. Finally, expression markers of cardiac remodeling are monitored by RT‐qPCR analysis and associate with DNA hydroxymethylation signature by DNA immunoprecipitation and correlation analyses. Conclusion Global changes of DNA hydroxymethylation in hearts of HFD‐fed mice are associated with upregulation of the dioxygenase Tet3 and decreased content of α‐ketoglutarate. A relation between Tet genes and markers of cardiac hypertrophic response is observed and, if further validated, it will provide insights concerning epigenetics and obesity‐related cardiac complications.

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Section: Resultsmentioning

confidence: 99%

High Dietary Fat Intake Affects DNA Methylation/Hydroxymethylation in Mouse Heart: Epigenetic Hints for Obesity‐Related Cardiac Dysfunction

Ciccarone

Castelli

Ioannilli

et al. 2018

Molecular Nutrition Food Res

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show abstract

“…In diffuse large B-cell lymphoma, D-2HG levels have been found to be elevated secondary to mutation of the enzyme D-2HG dehydrogenase ( D2HGDH )27, which has a physiological role of converting D-2HG to α-ketoglutarate. We therefore examined for mutations of D2HGDH , and its counterpart for L-2HG, L-2HG dehydrogenase (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer

Colvin

Nishida

Konno

et al. 2016

Sci Rep

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Deranged metabolism is a hallmark of cancer, playing a significant role in driving the disease process. One such example is the induction of carcinogenesis by the oncometabolite D-2 hydroxyglutarate (D-2HG), which is produced by the mutated enzyme isocitrate dehydrogenase (IDH) occurring in subsets of leukaemias and brain tumours. The oncogenic property of D-2HG appears to stem from its ability to interfere with the activities of α-ketoglutarate-dependent dioxygenases, including the Jumonji family histone demethylases. Here, we find in colorectal cancer cells that even in the absence of IDH mutation, the levels of D-2HG and its enantiomer L-2HG were elevated through glutamine anaplerosis. D-2HG, but not L-2HG, increased the trimethylation of histone H3 lysine 4 of the promoter region of ZEB1, a master regulator of epithelial-mesenchymal transition (EMT), and increased the expression of the ZEB1 gene to directly induce EMT in colorectal cancer cells. EMT promotes the ability of cancer cells to invade the local tissue and enter into the bloodstream, leading to distant organ metastasis. D-2HG levels were elevated in colorectal cancer specimens, particularly in those associated with distant metastasis, supporting the observations in vitro and implicating the contribution of D-2HG in metastasis, the major cause of death in this disease.

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“…Whole cell lysates from tumors (12) or cell lines were prepared as previously described (11) and detailed in Suppl. Methods.…”

Section: Methodsmentioning

confidence: 99%

Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas

Toledo

Qin

Cheng

et al. 2016

Clinical Cancer Research

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108

100

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Purpose Pheochromocytomas and paragangliomas (PPGLs) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. Experimental Design We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was used for microarray-based transcription, protein expression and histone methylation analysis by western blot or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. Results We detected mutations in chromatin remodeling genes, including histone-methyltransferases, histone-demethylases and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes mutations were also detected in the validation group. Additionally, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. Conclusions This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes.

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D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

Cited by 65 publications

References 46 publications

High Dietary Fat Intake Affects DNA Methylation/Hydroxymethylation in Mouse Heart: Epigenetic Hints for Obesity‐Related Cardiac Dysfunction

High Dietary Fat Intake Affects DNA Methylation/Hydroxymethylation in Mouse Heart: Epigenetic Hints for Obesity‐Related Cardiac Dysfunction

Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer

Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas

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