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R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling
Open accessAbstract
R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N 6-methyladenosine (m 6 A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m 6 A/MYC/CEBPA signaling.
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“Of these, up to 90% of diffuse intrinsic pontine gliomas (DIPG) harbour a point mutation in canonical ( HIST1H3B (H3.1)) or variant ( H3F3A (H3.3)) histone H3, resulting in a lysine 27 to methionine (K27M) substitution 101-103 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [103]
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MethodN6-methyladenosine-dependent regulation of messenger RNA stability
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“…R-2HG inhibits the increase in fat mass and the expression of FTO, thereby increasing the modification of m6A RNA in leukemia cells sensitive to R-2HG; thus, leading to further reduction in the stability of MYC/CEPPA transcripts, and ultimately suppressing the related pathways (Su et al., 2018).”
BackgroundRNA N6-Methyladenosine in Cancer Metastasis: Roles, Mechanisms, and Applications
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“Through m6A‐dependent binding, it can not only stabilize c‐Myc mRNA, but also improve the protein level of c‐Myc, consequently promoting the clone formation ability of AML cells (Feng et al., 2021).”
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BackgroundFTO facilitates colorectal cancer chemoresistance via regulation of NUPR1-dependent iron homeostasis
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IDH1 fine-tunes cap-dependent translation initiation
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RNA N6-methyladenosine methylation and skin diseases
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“For example, the FTO signaling inhibitor R-2HG sensitizes acute myeloid leukemia (AML) cells to a variety of first-line therapeutic agents such as all-trans-retinoic acid (ATRA), 5-azacytidine (5-Aza), and daunorubicin (DNR) (Su et al., 2018).”
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“R-2HG, a specific small molecule inhibitor of FTO, displays anti-leukemia activity by suppressing FTO/m6A/MYC signaling (Su et al., 2018).”
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“The MYC/CEBPA signaling pathway was then inhibited to prevent leukemia progression.(105) In addition, m(6)A modification can regulate deoxycholic acid in deoxycholic acid metabolism to inhibit gallbladder cancer.”
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“Notably, the m6A/m6Am ratio varies between genetically diverse AML cell lines as well as other cancer cells [12, 92, 94].”
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“Of note, exogenous 2-HG can inhibit proliferation and viability in some leukemia cell lines [38].”
BackgroundTargeting mitochondrial metabolism in acute myeloid leukemia
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“2-hydroxyglutarate are also known to inhibit α-KG-dependent dioxygenase enzyme involved in removal of N6-methyladenosine (m6A) and N6,2 ′ -O-dimethyladenosine (m6Am) from RNA (Jia et al. 2011; Mauer et al. 2017; Su et al. 2018).”
The Role of M6A Modification in Autoimmunity: Emerging Mechanisms and Therapeutic Implications
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Emerging Roles of Wild-type and Mutant IDH1 in Growth, Metabolism and Therapeutics of Glioma
Garrett, M. C., Fujii, Y., Osaka, N., Ito, D., Hirota, Y., & Sasaki, A. T. (2021) · Exon Publications eBooks · doi:10.36255/exonpublications.gliomas.2021.chapter4 · Cited by 14
Self-citationChen, X., Shi, L., Zhang, L., Cheng, Y., Xue, Z., Yan, J., & Jiang, H. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.11.030 · Cited by 13
Interaction between m6A methylation and noncoding RNA in glioma
Tao, N., Wen, T., Li, T., Luan, L., Pan, H., & Wang, Y. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01075-5 · Cited by 13
Self-citationNano-imaging agents for brain diseases: Environmentally responsive imaging and therapy
Liang, F., You, Q., Ma, X., Wang, H., Wang, C., He, Z., Yang, Y., & Zhu, L. (2023) · Nano Research · doi:10.1007/s12274-023-6149-1 · Cited by 13
Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A
Horton, J. R., Liu, X., Wu, L., Zhang, K., Shanks, J. R., Zhang, X., Rai, G., Mott, B. T., Jansen, D. J., Kales, S. C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00261 · Cited by 13
Molecular mechanisms for stemness maintenance of acute myeloid leukemia stem cells
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“wide-type leukemia rather than functions as an oncometabolite.(76) This might result from, to some extent, the heterogeneous genetic foundation of AML patients.”
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RNA Regulators in Leukemia and LymphomaPreprint
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“Last, the metabolite R-2-hydroxyglutarate (R-2HG) was shown to have antileukemic activity, by directly inhibiting FTO activity and increasing m(6)A levels in non-IDH-mutant lines (Su et al. 2018).”
BackgroundRNA epitranscriptomics: A promising new avenue for cancer therapy
Yang, C., Han, H., & Lin, S. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.12.008 · Cited by 13
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Small-molecule and peptide inhibitors of m6A regulators
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“CS1 and CS2 selectively bind and occupy the catalytic pocket of FTO, preventing m6A-modi fi ed oligonucleotides from entering the catalytic pocket, thereby inhibiting FTO-mRNA binding and reducing MYC/CEBPA while increasing RARA/ASB2 expression (158, 167).”
The AlkB Family: Potential Prognostic Biomarkers and Therapeutic Targets in Glioblastoma
Feng, S., Xu, Z., Peng, J., & Zhang, M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.847821 · Cited by 12
“reported that R-2HG displayed anti-tumor activity in leukemia and glioma through targeting FTO, leading to MYC mRNA decay and downregulation of MYC/CEBPA-associated oncogenic pathways (46).”
BackgroundThe Regulation of m6A Modification in Glioblastoma: Functional Mechanisms and Therapeutic Approaches
Deacon, S., Walker, L., Radhi, M., & Smith, S. J. (2023) · Cancers · doi:10.3390/cancers15133307 · Cited by 13
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“[96] meclofenamic acid (MA) and MA2 substrate binding site Inhibit the survival, growth and self-renewal of GBM cells.”
BackgroundSelf-citationTargeting RNA modifications with pharmacological agents: New frontiers in cancer therapy
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“L e u k a e m i a a n d g l i o m a [ 183 , 184 ] G l y c o l y s i s i s s u pp r e ss e d b y R - 2 H G i n s e n s i t i v e l e u k a e m i a c e ll s .”
RNA modifications in cancer immune therapy: regulators of immune cells and immune checkpoints
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Self-citationEpitranscriptomics and cervical cancer: the emerging role of m6A, m5C and m1A RNA modifications
Modi, A. D., Zahid, H., Southerland, A. C., & Modi, D. M. (2024) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2024.20 · Cited by 12
“Epitranscriptomic modifications are linked to various hallmarks of cancer including survival, growth, restoration, differentiation, stress adaptation, invasion and drug resistance (Refs 16, 17, 18).”
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Enhanced detection of RNA modifications in Escherichia coli utilizing direct RNA sequencing
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Self-citationResearch advances on epigenetics and cancer metabolism
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“肿瘤,但同时也上调了MYC、CEPBPA等基因 的mRNA的m6A修饰,后者被YTHDF2识别后降 解,抑制肿瘤的葡萄糖和氨基酸代谢[101]。 mRNA的 m6A修饰可以在转录后水平微调 基因表达,促进翻译并缓冲miRNA的抑制作用,”
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“…have mainly focused on regulating m6A RNA modification regulators through transfection experiments, which are difficult to translate to clinical trials or clinical practice; therefore, m6A RNA modification regulator agonists or antagonists should be searched in the future (Su et al., 2018).”
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Intertwined regulation between RNA m6A modification and cancer metabolism
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“This work was supported by National Science Foundation for Distinguished Young Scholar (82025003), National Natural Science Foundation of China (81970152) and the Fundamental Research Funds for the Central Universities (2042020kf0208) to HL. Abbreviation 30UTR 30 untranslated region AML acute myeloid leukemia APC aden…”
BackgroundInfluentialSelf-citationThe diverse role of RNA methylation in esophageal cancer
Meng, W., Han, Y., Li, B., & Li, H. (2023) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2023057 · Cited by 12
Molecular mechanisms of autophagic memory in pathogenic T cells in human arthritis
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Development and validation of m6A regulators’ prognostic significance for endometrial cancer
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“Increasing global m6A RNA modification in leukemia cells could decrease the stability of MYC and result in the suppression of MYC pathways [32].”
BackgroundThe curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches
Gruber, E., & Kats, L. M. (2023) · Biochemical Society Transactions · doi:10.1042/bst20230017 · Cited by 11
RNA modifications in pulmonary diseases
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Metadata
- Authors
- Su, R., Dong, L., Li, C., Nachtergaele, S., Wunderlich, M., Qing, Y., Deng, X., Wang, Y., Weng, X., Hu, C., Yu, M., Skibbe, J., Dai, Q., Zou, D., Wu, T., Yu, K., Weng, H., Huang, H., Ferchen, K., Qin, X., Zhang, B., Qi, J., Sasaki, A. T., Plas, D. R., Bradner, J. E., Wei, M., Marcucci, G., Jiang, X., Mulloy, J. C., Jin, J., He, C., & Chen, J.
- Affiliations
- University of Cincinnati (US)
- First Affiliated Hospital Zhejiang University (CN)
- Howard Hughes Medical Institute (US)
- Cincinnati Children's Hospital Medical Center (US)
- Chongqing Cancer Hospital (CN)
- City Of Hope National Medical Center (US)
- Harvard University (US)
- China Medical University (CN)
- Corresponding author
- Jin, Jie
- He, Chuan
- Chen, Jianjun
- ORCID
- Su, Rui
- Dong, Lei
- Li, Chenying
- Nachtergaele, Sigrid
- Wunderlich, Mark
- Qing, Ying
- Deng, Xiaolan
- Weng, Xiaocheng
- Hu, Chao
- Yu, Mengxia
- Skibbe, Jennifer
- Dai, Qing
- Zou, Dongling
- Wu, Tong
- Weng, Hengyou
- Huang, Huilin
- Ferchen, Kyle
- Qin, Xi
- Zhang, Bin
- Qi, Jun
- Sasaki, Atsuo T.
- Plas, David R.
- Bradner, James E.
- Wei, Minjie
- Marcucci, Guido
- Jiang, Xi
- Mulloy, James C.
- Jin, Jie
- He, Chuan
- Chen, Jianjun
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 172
- Issue
- 1-2
- Pages
- 90-105.e23
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5766423
- OpenAlex
- W2772792536
- Cited by
- 1,137
- References
- 43
- Citations by year
- 2026: 75 · 2025: 100 · 2024: 161 · 2023: 163 · 2022: 165 · 2021: 197 · 2020: 150 · 2019: 76 · 2018: 48
- FWCI
- 31.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA214965, CA211614, CA178454, CA182528, RM1 HG008935, GM071440, R50 CA211404, R01NS089815, R21NS100077)
- Foundation of Innovation Team for Basic and Clinical Research of Zhejiang Province (2011R50015)
- Academic and Research Committee of Cincinnati Children’s Hospital Medical Center
- Leukemia & Lymphoma Society
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation (DRG-2215-15)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- (R)-2-hydroxyglutarate, 2-hydroxyglutarate, FTO, N6-methyladenosine modification, c-Myc, CEBPA, leukemia, glioma, IDH1/2 mutation, oncometabolites, RNA stability, cell cycle arrest, apoptosis
- MeSH terms
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Adenosine, Animals, Antineoplastic Agents, Brain Neoplasms, Glioma, Glutarates, Humans, Leukemia, RNA Processing, Post-Transcriptional, Signal Transduction, Proto-Oncogene Proteins c-myc, Jurkat Cells, CCAAT-Enhancer-Binding Proteins, Cell Line, Tumor, Mice, HEK293 Cells
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