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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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“39 Recently, the dynamic m 6 A modi fi cation was reported as a critical epigenetic driver for TKI-toleranceinAMLandsorafenib-toleranceinlivercancer.”
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InfluentialSelf-citationm6A methylation modulates adipogenesis through JAK2-STAT3-C/EBPβ signaling.
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“Chromatin immunoprecipitation ChIP assays were performed using a ChIP kit from Merck Millipore (17-295) according to the manufacturer’s instructions.”
MethodWang, J., Zhang, J., Liu, H., Meng, L., Gao, X., Zhao, Y., Wang, C., Gao, X., Fan, A., Cao, T., et al. (2024) · 癌症：英文版 · doi:10.1002/cac2.12534 · Cited by 62
“The half-life of RNA was calculated as previously described [20].”
MethodGuan, Y., Tiwari, A. D., Phillips, J. G., Hasipek, M., Grabowski, D., Pagliuca, S., Gopal, P., Kerr, C. M., Ademà, V., Radivoyevitch, T., et al. (2020) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-20-0173 · Cited by 64
Targeting the RNA demethylase FTO for cancer therapy
Zhou, L., Xu, H., Huang, Y., & Yang, C. (2021) · RSC Chemical Biology · doi:10.1039/d1cb00075f · Cited by 64
Wu, W.-C., Wang, S., Liu, Q., Shan, T., Wang, X., Feng, J., & Wang, Y. (2020) · The FASEB Journal · doi:10.1096/fj.201901994r · Cited by 63
Self-citationLi, F., Wang, H., Huang, H., Zhang, L., Wang, D., & Wan, Y. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00994 · Cited by 61
“…as autophagy (Cui et al., 2017; Xiang et al., 2017; Dai et al., 2018; Jin et al., 2018; Deng et al., 2019; Han D. et al., 2019) and affecting many signaling pathways including p38/ERK pathway, β-catenin pathway as well as MYC/CEBPA pathway (Su et al., 2018; Zhou et al., 2018; Deng et al., 2019).”
BackgroundSelf-citationQin, S., Mao, Y., Xue, C., Xiao, J., Qin, Y., & Zhao, L. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.62767 · Cited by 61
“revealed that the tumor metabolite R-2HG could act as an inhibitor of FTO, leading to the increased methylation and decreased expression of c-MYC and CEBPA, thereby blocking proliferation, cell cycle and inducing apoptosis in AML and glioma cells [146].”
BackgroundLiu, H., Xu, L., Yue, S., Su, H., Chen, X., Liu, Q., Li, H., Liang, H., Chen, X., He, J., et al. (2024) · 癌症：英文版 · doi:10.1002/cac2.12595 · Cited by 61
“DARTS was conducted to the direct binding between Panobinostat and NAT10 in cellular following the published protocol [32].”
MethodSelf-citationWang, X., Chen, Z., Xu, J., Tang, S., An, N., Jiang, L., Zhang, Y., Zhang, S., Zhang, Q., Shen, Y., et al. (2022) · Cell Research · doi:10.1038/s41422-022-00650-w · Cited by 60
Du, J., Hou, K., Mi, S., Ji, H., Ma, S., Ba, Y., Hu, S., Xie, R., & Chen, L. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00208 · Cited by 60
YTHDF2 Inhibits Gastric Cancer Cell Growth by Regulating FOXC2 Signaling Pathway
Shen, X., Zhao, K., Xu, L., Cheng, G., Zhu, J., Gan, L., Wu, Y., & Zhuang, Z. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2020.592042 · Cited by 59
“Recent studies have found that YTHDF2 has the ability to degrade mRNAs of oncogenes and tumor suppressor genes in different tumors (Chen et al., 2018; Su et al., 2018; Zhong et al., 2019; Liu et al., 2020).”
BackgroundCross‐Talk between Oxidative Stress and m6A RNA Methylation in Cancer
Yang, B., & Chen, Q. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6545728 · Cited by 61
YTHDF2 is a potential target of AML1/ETO-HIF1α loop-mediated cell proliferation in t(8;21) AML
Chen, Z., Shao, Y.-L., Wang, L.-L., Lin, J., Zhang, J., Ding, Y., Gao, B.-B., Liu, D., & Gao, X. (2021) · Oncogene · doi:10.1038/s41388-021-01818-1 · Cited by 59
“To assess m(6)A changes in t(8;21) AML cells after YTHDF2 downregulation, we performed dot blot using anti-m(6)A antibody, which specifically and quantitatively measures m(6)A abundance [19], in mRNA from Kasumi-1 and SKNO-1 transfected with control scrambled siRNA or siRNA against YTHDF2.”
MethodWang, D., Qu, X., Lü, W., Wang, Y., Jin, Y., Hou, K., Yang, B., Li, C., Qi, J., Xiao, J., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.681280 · Cited by 57
Self-citationThe role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer
Shi, B., Liu, W.-W., Yang, K., Jiang, G., & Wang, H. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01634-5 · Cited by 58
“Moreover, FTO is reported to increase the stability of MYC mRNA by depressing the YTHDF2-mediated decay [85].”
BackgroundWang, L., Wu, L., Zhu, Z., Zhang, Q., Li, W., Gonzalez, G. M., Wang, Y., & Rana, T. M. (2022) · The EMBO Journal · doi:10.15252/embj.2022111673 · Cited by 58
Self-citationContributions and prognostic values of m6A RNA methylation regulators in non‐small‐cell lung cancer
Liu, Y., Guo, X., Zhao, M., Ao, H., Leng, X., Liu, M., Wu, C., Ma, J., & Zhu, J. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29531 · Cited by 57
“FTO is the first RNA demethylase identified in m6A RNA modification.”
BackgroundInfluentialRNA N-6-methyladenosine enzymes and resistance of cancer cells to chemotherapy and radiotherapy
Xiang, M., Liu, W., Tian, W., You, A., & Deng, D. (2020) · Epigenomics · doi:10.2217/epi-2019-0358 · Cited by 57
Regulatory role and mechanism of m6A RNA modification in human metabolic diseases
Zhang, Y., Chen, W., Zheng, X., Guo, Y., Cao, J., Zhang, Y., Wen, S., Gao, W., & Wu, Y. (2021) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2021.05.003 · Cited by 58
Non-Coding RNA m6A Modification in Cancer: Mechanisms and Therapeutic Targets
Da-hong, C., Zhang, J., Wu, C.-X., & Li, Q. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.778582 · Cited by 57
“It is well known that meclofenamic acid, R-2hydroxyglutarate, and MO-I-500 inhibit the activity of FTO and display anti-cancer activity (Huang et al., 2015; Singh et al., 2016; Su et al., 2018).”
BackgroundDynamic and reversible RNA N6‐methyladenosine methylation
Duan, H., Wang, Y., & Jia, G. (2018) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1507 · Cited by 59
“In accordance with the oncogenic role of FTO in AML, R-2-hydroxyglutarate (R-2HG), an endogenous inhibitor of FTO, can suppress leukemia progression in some sensitive AML cell lines (Su et al., 2017).”
BackgroundSelf-citationMetabolic Control of m6A RNA Modification
Kim, J., & Lee, G. (2021) · Metabolites · doi:10.3390/metabo11020080 · Cited by 57
Functions of RNA N6-methyladenosine modification in cancer progression
Chen, B., Li, Y., Song, R., Xue, C., & Xu, F. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-04655-4 · Cited by 57
Classification and function of RNA –protein interactions
Liu, S., Li, B., Qu, L., Liu, A., Qu, L., & Yang, J. (2020) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1601 · Cited by 56
Wang, J., Fu, Q., Yang, J. P., Liu, J., Hou, S., Huang, X., Cao, J., Liu, T., & Wang, K. (2021) · Aging · doi:10.18632/aging.203377 · Cited by 56
“functional stem cell differentiation, leading to neurogenesis retardation, immune deficiency, and sterility [10, 14, 15].”
BackgroundMetabolic adaptations in cancers expressing isocitrate dehydrogenase mutations
Hvinden, I. C., Cadoux-Hudson, T. A. D., Schofield, C. J., & McCullagh, J. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100469 · Cited by 63
“The slower proliferation rate ofmutIDH1 cells (comparedwith the WT) has also been reported for glioma cells derived from affected individuals(173) and human leukemic cells exposed to R-2-HG.(211) Currently, other than for elevated R-2-HG, it is difficult to form clear conclusions regarding metabolic adaptions in mutID…”
BackgroundInfluentialRNA modification systems as therapeutic targets
Zhang, L., Wei, J., Zou, Z., & He, C. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01280-8 · Cited by 64
Self-citationDeciphering the Epitranscriptome in Cancer
Lian, H., Wang, Q.-H., Zhu, C., Ma, J., & Jin, W. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.01.006 · Cited by 57
Bioinformatics approaches for deciphering the epitranscriptome: Recent progress and emerging topics
Liu, L., Song, B., Ma, J., Song, Y., Zhang, S.-Y., Tang, Y., Wu, X., Wei, Z. C., Chen, K., Su, J., et al. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.06.010 · Cited by 56
“…acid (R-2HG) increases the overall m 6 A level in R-2HG sensitive leukemia cells which in turn decreases the stability of MYC/CEBPA transcripts, leading to suppression of MYC/CEBPA-related signaling pathways and thus inhibition of the proliferation of FTO-highly expressed cancer cells [40].”
BackgroundHepatic FTO is dispensable for the regulation of metabolism but counteracts HCC development in vivo
Mittenbühler, M. J., Saedler, K., Nolte, H., Kern, L., Zhou, J. L., Qian, S., Meder, L., Ullrich, R. T., Brüning, J. C., & Wunderlich, F. T. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101085 · Cited by 56
METTL3 promotes cell cycle progression via m6A/YTHDF1-dependent regulation of CDC25B translation
Li, H., Zhong, Y., Cao, G., Shi, H., Liu, Y., Li, L., Yin, P., Chen, J., Xiao, Z., & Du, B. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.70335 · Cited by 55
“The genomic distribution of m6A peaks across mRNA transcripts and the m6A motifs identified from the two groups (Figure 3B-3D, mapped region of each sample are shown in Figure S1D) were consistent with those reported previously [28].”
ResultSelf-citationThe emerging roles of N6-methyladenosine RNA methylation in human cancers
Shen, H., Lan, Y., Zhao, Y., Shi, Y., Jin, J., & Xie, W. (2020) · Biomarker Research · doi:10.1186/s40364-020-00203-6 · Cited by 55
“R-2-hydroxyglutarate (R-2HG), a tumor suppressor, can inhibit the expression of FTO, providing us a novel imagination in AML treatment [130].”
BackgroundInfluentialSelf-citationLi, J., Pei, Y., Zhou, R., Tang, Z., & Yang, Y. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.56251 · Cited by 55
“It has since been shown that 138 inhibition of FTO can increase the level of m6A modification across all mRNAs [31].”
BackgroundSong, W., Yang, K., Luo, J., Gao, Z., & Gao, Y. (2021) · Aging · doi:10.18632/aging.202359 · Cited by 52
“Thereafter, FTO was shown to direct gene expression by changing the level of mRNA m6A methylation and acts as an oncogene in breast cancer [14], lung cancer [15, 16], endometrial cancer [17], acute myeloid leukemia [18, 19] as well as pancreatic cancer [20].”
BackgroundQin, S., Mao, Y., Wang, H., Duan, Y., & Zhao, L. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.60641 · Cited by 55
Wu, Z., Zuo, X., Zhang, W., Li, Y., Gui, R., Leng, J., Shen, H.-R., Pan, B., Fan, L., Li, J., et al. (2023) · Advanced Science · doi:10.1002/advs.202304895 · Cited by 60
The Tricarboxylic Acid Cycle Metabolites for Cancer: Friend or Enemy
Wu, J., Liu, N., Chen, J., Tao, Q., Li, Q., Li, J., Chen, X., & Peng, C. (2024) · Research · doi:10.34133/research.0351 · Cited by 57
“Studies have shown that in leukemia and glioma, 2-HG exerts antitumor effects by inhibiting fat mass and obesity-associated protein (FTO) involving in mRNA modification and downstream MYC/CCAAT enhancer binding protein alpha signaling [75].”
BackgroundSelf-citation
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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