α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer

Tran, Trac D.; Hanse, Eric A.; Habowski, Amber N.; Li, Haiqing; Gabra, Mari B. Ishak; Yang, Ying; Lowman, Xazmin H.; Ooi, Amelia M.; Liao, Shu-Yuan; Edwards, Robert A.; Waterman, Marian L.; Kong, Mei

doi:10.1038/s43018-020-0035-5

Cited by 103 publications

(100 citation statements)

References 62 publications

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“…In a recent study, the role of αKG as a signaling molecule in CRC was elucidated: the hypomethylation of DNA and histone H3K4me3, induced by αKG, led to an upregulation of differentiation-associated genes and a downregulation of Wnt target genes in an intestinal organoid model. The restriction of glutamine results in reduced αKG levels, which subsequently activates the Wnt pathway and promotes cancer stemness [ 137 ].…”

Section: Mitochondrial Metabolism Of Colorectal Cancermentioning

confidence: 99%

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel

Demuth

Wittmann

et al. 2020

Cancers

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Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

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Section: Mitochondrial Metabolism Of Colorectal Cancermentioning

confidence: 99%

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel

Demuth

Wittmann

et al. 2020

Cancers

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“…Notably, the effects of αKG extend beyond tissues that are prone to transformation by oncometabolites. In both intestinal and epidermal stem cells, αKG is sufficient for stem cell differentiation and can suppress tumor initiation and progression [7,26]. The effects of αKG extend to transformed cells: in pancreatic cancer cells, p53 restoration drives αKG-dependent differentiation, and αKG alone is sufficient to recapitulate the effects of p53 [84].…”

Section: Box 1 Cancer-associated Mutations Hijack Metabolic Control mentioning

confidence: 99%

“…In the liver, mutant IDH1 expression blunts progenitor differentiation into hepatocytes by silencing the master TF HNF4α [25]. In intestinal tumor organoids, αKG is sufficient to suppress activation of the master intestinal stem cell regulator β-catenin and induce differentiation [26]. Despite correlations with changes in DNA and histone methylation at TF promoters and target gene loci, the exact mechanisms by which metabolites affect expression and activity of these specific TFs are not well understood.…”

Section: Box 1 Cancer-associated Mutations Hijack Metabolic Control mentioning

confidence: 99%

Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases

Baksh

Finley

2021

Trends in Cell Biology

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Cell fate determination requires faithful execution of gene expression programs, which are increasingly recognized to respond to metabolic inputs. In particular, the family of α-ketoglutarate (αKG)-dependent dioxygenases, which include several chromatin-modifying enzymes, are emerging as key mediators of metabolic control of cell fate. αKG-dependent dioxygenases consume the metabolite αKG (also known as 2-oxoglutarate) as an obligate cosubstrate and are inhibited by succinate, fumarate, and 2-hydroxyglutarate. Here, we review the role of these metabolites in the control of dioxygenase activity and cell fate programs. We discuss the biochemical and transcriptional mechanisms enabling these metabolites to control cell fate and review evidence that nutrient availability shapes tissue-specific fate programs via αKG-dependent dioxygenases. Cell Fate Determination Responds to Metabolic Inputs Development and homeostasis of multicellular organisms depends on cells acquiring and maintaining the correct fate at the right place and time. Cell fate determination (see Glossary), wherein less differentiated cells progressively acquire specific fates and functions, is essential for proper embryogenesis and maintenance of postnatal tissue homeostasis by stem cells. In both the embryo and postnatal tissues, cell fate determination depends both on inductive signals from the environment and the competence of cells to respond appropriately to these signals [1,2]. Accordingly, dysregulation of either extracellular cues or their downstream intracellular responses compromise cell fate programs and results in diseases ranging from birth defects to cancer [1,2]. Consequently, dissecting the molecular regulation of cell fate decisions is critically important for understanding the mechanistic basis of both normal physiology and disease states. Increasingly, metabolites are recognized as important modulators of the regulatory programs that control cell fate. In particular, chemical modifications on DNA and histones provide a critical avenue for cells to control activation of gene expression programs that specify cell identity [3]. These chemical modifications are derived from intermediates of cellular metabolism, most notably S-adenosylmethionine and acetyl-CoA, which serve as the donors for methylation and acetylation modifications, respectively. Enzymes that remove these modifications often also require metabolites as critical cosubstrates. Accordingly, fluctuations in the availability of key metabolites that modulate activity of chromatin-modifying enzymes are postulated to contribute to transcriptional regulation by shaping the chromatin landscape [4]. Intracellular metabolite levels are responsive to both cell-intrinsic metabolic pathway activity as well as extrinsic cues from the microenvironment, including growth factors and nutrient availability. Many inputs, including tissue lineage, proliferative status, and nutrient availability, collectively determine the metabolic demands of individual cells [5]. In turn, cell type-specific me...

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“…In particular, some epigenetic effectors, such as the ten eleven translocation hydroxylases (TETs), enzymes promoting DNA demethylation, and the Jumonji C domain-containing lysine demethylases (JmjC-KDMs or JHDMs), acting on lysine residues of histone proteins, are members of 2-OGDO family and their activity is αKG-dependent. Thus, αKG availability influences and regulates epigenetic processes with consequences for the expression of some regulatory genes involved in cellular pluripotency and differentiation [65][66][67], as well as in oncogenic signaling correlated with stemness [68].…”

Section: The Role Of Wild-type Idh1 In Cellular Processesmentioning

confidence: 99%

IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

et al. 2020

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Cholangiocarcinoma is a primary malignancy of the biliary tract characterized by late and unspecific symptoms, unfavorable prognosis, and few treatment options. The advent of next-generation sequencing has revealed potential targetable or actionable molecular alterations in biliary tumors. Among several identified genetic alterations, the IDH1 mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some IDH1 point mutations induce widespread epigenetic alterations by means of a gain-of-function of the enzyme, which becomes able to produce the oncometabolite 2-hydroxyglutarate, with inhibitory activity on α-ketoglutarate-dependent enzymes, such as DNA and histone demethylases. Thus, its accumulation produces changes in the expression of several key genes involved in cell differentiation and survival. At present, small-molecule inhibitors of IDH1 mutated enzyme are under investigation in preclinical and clinical phases as promising innovative treatments for IDH1-mutated intrahepatic cholangiocarcinomas. This review examines the molecular rationale and the results of preclinical and early-phase studies on novel pharmacological agents targeting mutant IDH1 in cholangiocarcinoma patients. Contextually, it will offer a starting point for discussion on combined therapies with metabolic and epigenetic drugs, to provide molecular support to target the interplay between metabolism and epigenetics, two hallmarks of cancer onset and progression.

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α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer

Cited by 103 publications

References 62 publications

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases

IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

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