R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis

Qing, Ying; Dong, Lei; Gao, Lei; Li, Chenying; Li, Yangchan; Liang, Han; Prince, Emily; Tan, Brandon; Deng, Xiaolan; Wetzel, Collin; Shen, Chao; Gao, Min; Chen, Zhenhua; Li, Wei; Zhang, Bin; Braas, Daniel; Hoeve, Johanna ten; Sánchez, Gerardo; Chen, Huiying; Chan, Lai N.; Chen, Chun-Wei; Ann, David K.; Jiang, Lei; Müschen, Markus; Marcucci, Guido; Plas, David R.; Li, Zejuan; Su, Rui; Chen, Jianjun

doi:10.1016/j.molcel.2020.12.026

Cited by 215 publications

(173 citation statements)

References 98 publications

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“…The third step of aerobic glycolysis relies on the catalysis of phosphofructokinase. Studies have found that under the inhibition of R-2-hydroxyglutarate, the activity of FTO decreases, and m6A modification can degrade platelet phosphofructokinase (PFKP) and lactate dehydrogenase B (LDHB) mRNA through the YTHDF2dependent pathway, thereby inhibiting oxygen glycolysis [156]. In addition, the expression of MYC, a regulator of glycolysis, is also enhanced by the IGF2BP2-dependent m6A modification pathway.…”

Section: N6-methyladenosine Cancer Plays a Role In Metabolic Reprogrammingmentioning

confidence: 99%

N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

Tan

Zhao

Xiong

et al. 2021

J Exp Clin Cancer Res

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The N6-methyladenosine (m6A) modification is a dynamic and reversible epigenetic modification, which is co-transcriptionally deposited by a methyltransferase complex, removed by a demethylase, and recognized by reader proteins. Mechanistically, m6A modification regulates the expression levels of mRNA and nocoding RNA by modulating the fate of modified RNA molecules, such as RNA splicing, nuclear transport, translation, and stability. Several studies have shown that m6A modification is dysregulated in the progression of multiple diseases, especially human tumors. We emphasized that the dysregulation of m6A modification affects different signal transduction pathways and involves in the biological processes underlying tumor cell proliferation, apoptosis, invasion and migration, and metabolic reprogramming, and discuss the effects on different cancer treatment.

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Section: N6-methyladenosine Cancer Plays a Role In Metabolic Reprogrammingmentioning

confidence: 99%

N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

Tan

Zhao

Xiong

et al. 2021

J Exp Clin Cancer Res

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“…As a consequence, tumor cell proliferation is impaired (Su et al, 2018). Inhibition of FTO by R-2-HG also ameliorates aerobic glycolysis by increasing m 6 A levels in the mRNA of phosphofructokinase (PFKP) and LDHB, which reduces the expression of PFKP and LDHB (Qing et al, 2021). α-Etoglutarate Dehydrogenase Complex α-ketoglutarate dehydrogenase complex (α-KGDHC) is the third rate-limiting enzyme in the TCA cycle, which is composed of α-KG dehydrogenase (OGDH), dihydrolipidamide S-succinyltransferase (DLST) and dihydrolipidamide dehydrogenase (DLD).…”

Section: Isocitrate Dehydrogenasementioning

confidence: 99%

Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer

et al. 2021

Front. Cell Dev. Biol.

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Cancer cells reprogram glucose metabolism to meet their malignant proliferation needs and survival under a variety of stress conditions. The prominent metabolic reprogram is aerobic glycolysis, which can help cells accumulate precursors for biosynthesis of macromolecules. In addition to glycolysis, recent studies show that gluconeogenesis and TCA cycle play important roles in tumorigenesis. Here, we provide a comprehensive review about the role of glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on revealing the novel functions of the relevant enzymes and metabolites. These functions include regulation of cell metabolism, gene expression, cell apoptosis and autophagy. We also summarize the effect of glucose metabolism on chromatin modifications and how this relationship leads to cancer development. Understanding the link between cancer cell metabolism and chromatin modifications will help develop more effective cancer treatments.

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“…In addition, METTL14 is critical for normal hematopoiesis, as it enhances the mRNA stability and translation of the oncogenic transcription factors MYB and MYC, while METTL14 itself is negatively regulated by SPI1 [ 69 ]. However, FTO is dispensable for normal HSPCs [ 73 ]. In addition, ALKBH5 does not affect normal hematopoietic function in the steady state and plays only a very minor role in maintaining HSC self-renewal and differentiation under competitive repopulation stress [ 76 , 77 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown to suppress FTO activity, increase the global m 6 A modification level and exert antitumor effects in AML without IDH1/2 mutations by decreasing the mRNA stability of MYC/CEBPA, leading to the suppression of related pathways [ 53 ]. R-2HG also effectively suppresses aerobic glycolysis in IDH-wild-type leukemia cells by targeting the FTO/m 6 A/YTHDF2 signaling pathway to downregulate the expression of two critical glycolytic genes, PFKP and LDHB, which contributes to its antitumor effects [ 73 ]. Meclofenamic acid (MA), a nonsteroidal anti-inflammatory drug, has been identified as a highly selective inhibitor of FTO over ALKBH5 [ 92 ].…”

Section: Introductionmentioning

confidence: 99%

Functions of RNA N6-methyladenosine modification in acute myeloid leukemia

Zheng

Gong

2021

Biomark Res

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Acute myeloid leukemia (AML) is a hematologic malignancy with an unfavorable prognosis. A better understanding of AML pathogenesis and chemotherapy resistance at the molecular level is essential for the development of new therapeutic strategies. Apart from DNA methylation and histone modification, RNA epigenetic modification, another layer of epigenetic modification, also plays a critical role in gene expression regulation. Among the more than 150 kinds of RNA epigenetic modifications, N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in eukaryotes and is involved in various biological processes, such as circadian rhythms, adipogenesis, T cell homeostasis, spermatogenesis, and the heat shock response. As a reversible and dynamic modification, m6A is deposited on specific target RNA molecules by methyltransferases and is removed by demethylases. Moreover, m6A binding proteins recognize m6A modifications, influencing RNA splicing, stability, translation, nuclear export, and localization at the posttranscriptional level. Emerging evidence suggests that dysregulation of m6A modification is involved in tumorigenesis, including that of AML. In this review, we summarize the most recent advances regarding the biological functions and molecular mechanisms of m6A RNA methylation in normal hematopoiesis, leukemia cell proliferation, apoptosis, differentiation, therapeutic resistance, and leukemia stem cell/leukemia initiating cell (LSC/LIC) self-renewal. In addition, we discuss how m6A regulators are closely correlated with the clinical features of AML patients and may serve as new biomarkers and therapeutic targets for AML.

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R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis

Cited by 215 publications

References 98 publications

N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer

Functions of RNA N6-methyladenosine modification in acute myeloid leukemia

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