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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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“On the other hand, R-2-hydroxyglutaric acid (R-2HG) can stabilize the expression of MYC/CEBPA mRNA by inhibiting FTO demethylation and blocking mRNA degradation mediated by the m(6)A binding protein YTHDF2, thus inhibiting the proliferation of AML cells (50).”
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Self-citationRNA m6A modification: a key regulator in normal and malignant processes
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“The activities of RNA-mod-ifying enzymes (e.g., FTO and ALKBH5) are modulated by S-adenosylmethionine (SAM) and α-ketoglutarate (α-KG): SAM donates methyl groups for methylation [60], whereas α-KG serves as a demethylase cofactor, regulating RNA modification dynamics [61].”
Recent advances in functional annotation and prediction of the epitranscriptome
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Self-citationThe Role of N6‐Methyladenosine in Inflammatory Diseases
Xu, H., Lin, C., Yang, J., Chen, X., Chen, Y., Chen, J., Guo, A., & Hu, C. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/9744771 · Cited by 19
Self-citationZhu, X., Fu, H., Sun, J., & Xu, Q. J. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110376 · Cited by 18
The role of m6A RNA methylation in autoimmune diseases: Novel therapeutic opportunities
Shan, Y., Chen, W., & Li, Y. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.02.013 · Cited by 19
Zhang, Q., Qian, Y.-M., Ren, Y., Chen, M.-M., Cao, L., Zheng, S., Li, B., Wang, M., Wu, X., & Xu, K. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01178-4 · Cited by 18
The role of m6A demethylases in lung cancer: diagnostic and therapeutic implications
Yu, M., Ji, W., Xu, Y., Tian, K., Ma, X., Yu, S., Chen, L., & Zhao, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1279735 · Cited by 18
Self-citationRewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma
Fitzsimmons, C. M., Mandler, M. D., Lunger, J. C., Chan, D., Maligireddy, S. S., Schmiechen, A. C., Gamage, S. T., Link, C. N., Jenkins, L. M. M., Chan, K. C., et al. (2024) · NAR Cancer · doi:10.1093/narcan/zcae004 · Cited by 18
RBM15 Protects From Myocardial Infarction by Stabilizing NAE1
Cheng, H., Wu, J., Li, L., Song, X., Xue, J., Shi, Y., Zou, Y., Ma, J., & Ge, J. (2024) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2024.01.017 · Cited by 18
Decoding the specificity of m6A RNA methylation and its implication in cancer therapy
Cun, Y., Guo, W., Ma, B., Okuno, Y., & Wang, J. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.05.035 · Cited by 17
The Role of N6-methyladenosine Modification in Gametogenesis and Embryogenesis: Impact on Fertility
Wang, Y., Yang, C., Sun, H., Jiang, H., Zhang, P., Huang, Y., Liu, Z., Yu, Y., Xu, Z., Xiang, H., et al. (2024) · Genomics Proteomics & Bioinformatics · doi:10.1093/gpbjnl/qzae050 · Cited by 20
“The FTO inhibitors R-2HG and FB23-2 can inhibit the growth of leukemia cells and slow the progression of leukemia; FB23-2 is more effective and can significantly inhibit acute myeloid leukemia progression in xenograft mice [163,164].”
BackgroundSelf-citationMethyladenosine Modification in RNAs: Classification and Roles in Gastrointestinal Cancers
Li, Q., He, W., & Wan, G. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.586789 · Cited by 18
Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer
Ma, R., Wu, Y., Li, S., & Yu, X. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.654337 · Cited by 18
“As a consequence, tumor cell proliferation is impaired (Su et al., 2018).”
BackgroundInfluentialFunctions of RNA N6-methyladenosine modification in acute myeloid leukemia
Zheng, X. Y., & Gong, Y. (2021) · Biomarker Research · doi:10.1186/s40364-021-00293-w · Cited by 19
“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].”
BackgroundInfluentialAn Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality
Mueller, S., Dennison, G., & Liu, S. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18136930 · Cited by 18
Advances in the Immunotherapeutic Potential of Isocitrate Dehydrogenase Mutations in Glioma
Tang, F. R., Pan, Z., Wang, Y., Lan, T., Wang, M., Li, F., Quan, W., Liu, Z., Wang, Z., & Li, Z. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00866-1 · Cited by 18
Self-citationRNA modification in normal hematopoiesis and hematologic malignancies
Chen, X., Yuan, Y., Zhou, F., Li, L., Pu, J., & Jiang, X. (2024) · MedComm · doi:10.1002/mco2.787 · Cited by 17
Self-citationFTO degrader impairs ribosome biogenesis and protein translation in acute myeloid leukemia
Li, W., Zhao, Y., Wu, D., Chen, Z., Qing, Y., Yang, F., Ji, F., Zhang, L., Sau, L., Chen, J., et al. (2025) · Science Advances · doi:10.1126/sciadv.adv7648 · Cited by 17
“In addition, FTO enhances the stability of MYC and CEBPA mRNAs by erasing their m 6 A marks, thereby facilitating their oncogenic roles ( 15 ).”
Self-citationm6A Modifications Play Crucial Roles in Glial Cell Development and Brain Tumorigenesis
Wang, J., Sha, Y., & Sun, T. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.611660 · Cited by 17
“org 6 protein alpha (CEBPA) in glioma, especially IDH1/2 mutant glioma (71).”
BackgroundThe role of regulators of RNA m6A methylation in lung cancer
Zhang, Q., & Xu, K. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2021.12.017 · Cited by 17
“It enhances the YTHDF2 mediated degradation of MYC and CEBPA, and causes cell growth inhibition, cell-cycle arrest and apoptosis of acute myelocytic leukemia (AML).(99) In addition, R-2HG also exerts synergistic effects with other chemotherapy drugs against leukemia and glioma.”
BackgroundKisan, A., & Chhabra, R. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30907 · Cited by 17
“For example, in tumor cells, inhibitors of FTO demethylase like meclofenamic acid (Y. Huang et al., 2015)and R‐2HG (Su et al., 2018) reduced cell proliferation and induced programmed cell death.”
BackgroundInsights into the role of RNA m6A modification in the metabolic process and related diseases
Hu, H., Li, Z., Xie, X., Liao, Q., Hu, Y., Gong, C., Gao, N., Yang, H., Xiao, Y., & Chen, Y. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.04.038 · Cited by 17
“48 In summary, m 6 A modification regulates RNA metabolism via multiple pathways, and the outcomes of m 6 A-modified RNAs are distinct depending on tissue and cell type.”
BackgroundLiu, Q., Qi, J., Li, W., Tian, X., Zhang, J., Liu, F., Lu, X., Zang, H., Liu, C., Ma, C., et al. (2023) · Cancer Cell International · doi:10.1186/s12935-023-03096-1 · Cited by 17
“In acute myeloid leukemia (AML), METTL3 promotes leukemogenesis and inhibits myeloid differentiation, potentially through the targeting of oncogenic genes such as MYC and CEBPA [22, 23].”
BackgroundSelf-citationYao, Y., Liu, P., Li, Y., Wang, W., Jia, H., Bai, Y., Yuan, Z., & Yang, Z. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116171 · Cited by 17
RNA methylation‐related inhibitors: Biological basis and therapeutic potential for cancer therapy
Chen, H., Liu, H., Zhang, C., Xiao, N., Yang, L., Zhao, X., Zhang, R., Gu, H., Kang, Q., & Wan, J. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.1644 · Cited by 17
“16 However, there are relatively few studies on m5C inhibitors, and most of them target methyltransferase NSUN2, so the subsequent development of m5C inhibitors is also very promising.”
BackgroundArrè, V., Mastrogiacomo, R., Balestra, F., Serino, G., Viti, F., Rizzi, F. R., Curri, M. L., Giannelli, G., Depalo, N., & Scavo, M. P. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16040567 · Cited by 17
“…and c(RGDyC) modification to deliver short RNAi against YTHDF1: a novel therapeutic strategy for GC via epigenetic and immune regulation [155,166] colon IBD EVs released by MSCs and loaded with miR-146: a new strategy in the treatment of IBD in mouse models [126] EVs and bacteria-derived…”
BackgroundZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation
Hu, Q., Yin, J., Zhao, S., Wang, Y., Shi, R., Yan, K., & Huang, S. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02060-w · Cited by 18
“In acute myeloid leukemia (AML), much evidence shows that FTO demethylase is highly expressed and performs an oncogenic role in promoting cell proliferation and inhibiting apoptosis [27 – 29].”
BackgroundSelf-citationRegulations of m6A and other RNA modifications and their roles in cancer
Chen, X., Guo, K., Li, J., Xu, S., Zhu, H., & Yan, G. (2024) · Frontiers of Medicine · doi:10.1007/s11684-024-1064-8 · Cited by 18
Shi, Y., Lei, Y., Chen, M., Ma, H., Shen, T., Zhang, Y., Huang, X., Ling, W., Liu, S., Pan, Y., et al. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c12884 · Cited by 17
Moshitch-Moshkovitz, S., Sevilla-Sharon, M., Ashwal-Fluss, R., Glick‐Saar, E., Rechavi, G., & Dominissini, D. (2024) · Nature Reviews Methods Primers · doi:10.1038/s43586-024-00365-9 · Cited by 19
The m6A(m)-independent role of FTO in regulating WNT signaling pathways
Kim, H., Jang, S., & Lee, Y.-S. (2022) · Life Science Alliance · doi:10.26508/lsa.202101250 · Cited by 18
“Contrary to FTO ’ s well-known role in mRNA demethylation (Jia et al, 2011; Wei et al, 2018) and mRNA stability (Su et al, 2018; Kim et al, 2021), we fi nd no signi fi cant change in DKK1 mRNA methylation and stability in FTO-depleted cells.”
Lobato, M. N., Royce, S. E., & Mohle‐Boetani, J. C. (2003) · PubMed · Cited by 17
Guang, L., Ma, S., Yao, Z., Song, D., Chen, Y., Liu, S., Wang, P., Su, J., Wang, Y., Luo, L., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-53820-2 · Cited by 19
“…results suggest a unique mechanism for the FTO rs9939609-A SNP, which increases a human muscle-speci fi c FTO enhancer ’ s activity, and thus human muscle FTO demethylase levels to facilitate the m 6 A demethylationof IGF2 mRNA,whichhasbeenshowntoincreasemRNA stability and protein expression 43 .”
Self-citationZhao, Y., Chen, X., Zhang, X., & Liu, H. (2025) · Biomarker Research · doi:10.1186/s40364-025-00794-y · Cited by 18
Kumari, S., Kumar, S., & Muthuswamy, S. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-022-04158-z · Cited by 16
Abdollahi, S., Ardekanizadeh, N. H., Poorhosseini, S. M., Gholamalizadeh, M., Roumi, Z., Goodarzi, M. O., & Doaei, S. (2022) · Advances in Nutrition · doi:10.1093/advances/nmac101 · Cited by 17
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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