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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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Items 401–500 of 1,000
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BackgroundSelf-citationM6AREG: m6A-centered regulation of disease development and drug response
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“Moreover, R-2HG inhibits GBM tumor outgrowth and ameliorates tumor survival in vitro and in vivo by hindering FTO activity [218].”
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“FTO may however exhibit an oncogenic role as well, by sustaining the stability of c-Myc and CCAAT enhancer binding protein alpha (CEBPA) glioma transcripts, especially in IDH1/2 mutant cases [70, 71].”
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Liang, Y., Zhan, G., Chang, K.-J., Yang, Y., Wang, L., Lin, J., & Hsu, C.-H. (2020) · Journal of the Chinese Medical Association · doi:10.1097/jcma.0000000000000251 · Cited by 33
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“Several studies have suggested a correlation between m6A and various cancers, including urologic neoplasms, digestive system neoplasms, and hematological cancer (Chen et al., 2018; Su et al., 2018; Chen et al., 2019; Han et al., 2019; Paris et al., 2019; Wang Q. et al., 2020).”
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Role of N6-methyladenosine methylation in glioma: recent insights and future directions
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“However, D-2HG may exert an anti-tumor effect by increasing the level of m6A methylation modification [99].”
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“As a novel epigenetic machinery, m6A has been shown to regulate gene expression by modulating pre-mRNA splicing, mRNA stability, RNA structure, and pre-miRNA processing (Lopez et al., 2014; Sales et al., 2011; Tadic et al., 2014).”
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Self-citationRNA N6-methyladenosine modification in solid tumors: new therapeutic frontiers
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Self-citationm6A RNA Methylation in Systemic Autoimmune Diseases—A New Target for Epigenetic-Based Therapy?
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“The oncometabolite R-2 hydroxyglutarate (R-2HG), able to target FTO/m6A/MYC/CEBPA signaling, restrained leukemia cell proliferation, cell cycle and induced cell apoptosis [217].”
BackgroundEpigenetic regulation of N6‐methyladenosine modifications in obesity
Sun, M., & Zhang, X. (2021) · Journal of Diabetes Investigation · doi:10.1111/jdi.13571 · Cited by 32
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“For example, R-2HG, an inhibitor of demethylase FTO, combined with chemotherapy drugs, was found to exert synergistic anticancer effects against leukemia and glioma in vivo and in vitro [47,48].”
BackgroundThe regulatory role of N6 ‐methyladenosine modification in the interaction between host and microbes
Zhuo, R., Xu, M., Wang, X., Zhou, B., Wu, X., Leone, V., Chang, E. B., & Zhong, X. (2022) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1725 · Cited by 31
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“In contrast, Chen et al demonstrated D-2HG exerted a broad antileukemic activity through FTO/m6A/MYC/ CEBPA signaling.(24) However, more investigations are needed into 2HGrelated targets as well as the effects on tumor progression.”
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“R-2HG has been shown to inhibit FTO-mediated m(6)A demethylation.(79) These compounds could be repurposed to modulate inflammatory responses.”
BackgroundRNA-modifying enzymes and their function in a chromatin context
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“A decreased (R)-2-HG level in e-cig users was found, and (R)-2HG has been proved to exhibit as an oncometabolite which is capable of inhibiting tumor growth [40].”
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RNA modifications in the tumor microenvironment: insights into the cancer-immunity cycle and beyond
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Self-citationComprehensive in vivo identification of the c-Myc mRNA protein interactome using HyPR-MS
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Epitranscriptomic Modifications Modulate Normal and Pathological Functions in CNS
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“We then examined the FTO expression in R-2HG-treated CCA cells, as a recent study indicated that R-2HGmight induce a high m6A level via degrading FTO, which is the first mRNA demethylase studied.(43,44) We checked the FTO expression in the R-2HG-treated CCA cells, and the results of western blot (Figure 6G) showed tha…”
BackgroundSelf-citationMiR-155 regulates m6A level and cell progression by targeting FTO in clear cell renal cell carcinoma
Yang, W., Xie, L., Wang, P., & Zhuang, C. (2021) · Cellular Signalling · doi:10.1016/j.cellsig.2021.110217 · Cited by 30
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“…14 (METTL14) [15, 16] and Wilms’ tumor 1-associating protein (WTAP) [17]), erasers (i.e., fat mass and obesity-associated protein (FTO) [18, 19] and α-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5) [20, 21]), and readers (i.e., YTH domain family 2 (YTHDF2) [22, 23]) are found…”
BackgroundDiscovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy
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Self-citationN6-Methyladenosine: an RNA modification as a central regulator of cancer
Luo, H., Kharas, M. G., & Jaffrey, S. R. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00889-6 · Cited by 34
“In AML, FTO overexpression supports leukaemia progression by blocking myeloid differentiation, enhancing aerobic glycolysis and sustaining leukaemic stem cell renewal 73,120,135,136 .”
InfluentialMYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome
Qiu, Z., Lin, A., Jiang, S., Elkashef, S. M., Myers, J., Srikantan, S., Sasi, B. K., Cao, J. Z., Godley, L. A., Rakheja, D., et al. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.02.002 · Cited by 31
“However, recent evidence suggests that in AML, D-2-HG may in fact have anti-tumor activity(Su et al., 2018).”
BackgroundThe momentous role of N6‐methyladenosine in lung cancer
Xu, R., Pang, G., Zhao, Q., Yang, L., Chen, S., Jiang, L., Shen, Y., & Shao, W. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.30136 · Cited by 29
The N6-methyladenosine RNA modification in acute myeloid leukemia
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“Other studies have suggested that FTO positively regulates the expression of AML oncogenes such as MYB and CEBPA [32].”
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“, Wilm’s tumor 1-related protein (WTAP), RNA binding motif protein 15 (RBM15), YTH domain (YTHs), and heterogeneous nuclear ribonucleoproteins (HNRNPs)] are involved in the progression of malignant tumors by recognizing m6A upon the reading, erasing, or writing of binding RNA in different tumors [20].”
BackgroundRoles of N6‐Methyladenosine Demethylase FTO in Malignant Tumors Progression
Zheng, Q.-K., Ma, C., Ullah, I., Hu, K., Ma, R., Zhang, N., & Sun, Z. (2021) · OncoTargets and Therapy · doi:10.2147/ott.s329232 · Cited by 29
“and in vivo via suppressing MYC/CEBPA signaling pathway by increasing the level of m6A mRNA.(67) R-2HG also”
Backgroundm6A Methylases Regulate Myoblast Proliferation, Apoptosis and Differentiation
Yang, X., Mei, C., Ma, X., Du, J., Wang, J., & Zan, L. (2022) · Animals · doi:10.3390/ani12060773 · Cited by 29
“Similarly, FTO was found to inhibit the proliferation of leukemic cells [31].”
BackgroundN6-methyladenosine RNA methylation: From regulatory mechanisms to potential clinical applications
Li, P., Wang, Y., Sun, Y., Jiang, S., & Li, J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1055808 · Cited by 30
Self-citationImmunotherapeutic Potential of m6A-Modifiers and MicroRNAs in Controlling Acute Myeloid Leukaemia
Kumar, S., Nagpal, R., Kumar, A., Ashraf, M. U., & Bae, Y. (2021) · Biomedicines · doi:10.3390/biomedicines9060690 · Cited by 29
RNA N6-methyladenosine modifications in urological cancers: from mechanism to application
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Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia
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Advances in the role of m6A RNA modification in cancer metabolic reprogramming
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METTL3/14 and IL‐17 signaling contribute to CEBPA‐DT enhanced oral cancer cisplatin resistance
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The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies
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“Previous research has shown that FTO played an important role in cell proliferation and inflammation [8, 10, 14, 28].”
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Metabolic Regulation of the Epitranscriptome
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“m(6)A eraser FTO removes m(6)A modification (Mathiyalagan et al., 2019; Mauer et al., 2017; Su et al., 2018)”
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“For example, 2-HG interferes with the activity of the fat mass and obesity-associated protein, leading to a reduction in N6-methy-ladenosine RNA modification and decreased stability of MYC / CEBPA transcripts, exhibiting antitumor effects [20].”
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“The median overall survival (OS) of patients with glioblastoma (GBM; WHO grade IV) is only approximately 15 months (1, 3, 4).”
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“R-2HG was found to inhibit FTO activity through elevating the global level of m6A in R-2HG-sensitive leukaemia cells, thus leading to the suppression of the stability of MYC and CEBPA [107].”
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“R-2HG, as a metabolite produced by mutant isocitrate dehydrogenases (IDHs), can inhibit FTO activity to increase the accumulation of m6A modified m6A in MYC transcripts of sensitive leukemia cells, resulting in decreased stability of MYC mRNA and downregulation of MYC signaling pathway [117].”
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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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