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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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Zhou, Z., Lv, J., Yu, H., Han, J., Yang, X. F., Feng, D., Wu, Q., Yuan, B., Lü, Q., & Yang, H. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01216-3 · Cited by 276
“The phenotypic differences associated with METTL3 may be explained by a differing reliance on m6A-modified RNAs in different types of GBM cells and differences in genetic heterogeneity.”
BackgroundInfluentialFTO controls reversible m6Am RNA methylation during snRNA biogenesis
Mauer, J., Sindelar, M., Despic, V., Guez, T., Hawley, B. R., Vasseur, J., Rentmeister, A., Gross, S. S., Pellizzoni, L., Debart, F., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0231-8 · Cited by 274
RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential
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RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer
Zhou, Y., Wang, T., Wu, D., Min, Z., Tan, J., & Yu, B. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01714-8 · Cited by 266
An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis
Zhu, S., Wang, J.-Z., Chen, D., He, Y., Meng, N., Chen, M., Lu, R., Chen, X., Zhang, X., & Yan, G. (2020) · Nature Communications · doi:10.1038/s41467-020-15403-9 · Cited by 270
Limits in the detection of m6A changes using MeRIP/m6A-seq
McIntyre, A. B. R., Gokhale, N. S., Cerchietti, L. C. A., Jaffrey, S. R., Horner, S. M., & Mason, C. E. (2020) · Scientific Reports · doi:10.1038/s41598-020-63355-3 · Cited by 259
“We could not compare our approach to results reported by Su et al. (2018), who found 6,024 peaks changed with R2HG treatment, Zeng et al. (2018), who found 465-599 peaks changed between tumour samples, or Ma et al. (2018), who found 12,452 peaks were gained and 11,192 lost between P7 and P20 mouse…”
ResultRegulation of Gene Expression by N-methyladenosine in Cancer
Liu, J., Harada, B. T., & He, C. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.02.008 · Cited by 251
“For example, the FTO inhibitor R-2-hydroxyglutarate (R-2HG) exhibits an antitumor activity in AML cells [76].”
BackgroundSelf-citationFTO in cancer: functions, molecular mechanisms, and therapeutic implications
Li, Y., Su, R. J., Deng, X., Chen, Y., & Chen, J. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.02.010 · Cited by 255
Self-citationLan, Q., Liu, P. Y., Bell, J. L., Wang, J. Y., Hüttelmaier, S., Zhang, X. D., Zhang, L., & Liu, T. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-4107 · Cited by 247
“YTHDF2 mediates c-Myc, CEBPA, and SOCS2 mRNA m(6)A modification to enhance c-Myc and CEBPA mRNA stability and to induce SOCS2 mRNA degradation, leading to leukemia and lung cancer cell proliferation and oncogenesis (19, 66).”
BackgroundShi, H., Chai, P., Jia, R., & Fan, X. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01194-6 · Cited by 256
“Moreover, by constraining YTHDF2-mediated decay, FTO decreases m(6)A frequency on MYC mRNA [109], METTL3 promotes translation of BCL2 and PTEN mRNA by upregulating the m(6)A levels and supports expression of SP1 by binding to the unique region with the help of the Table 2 mRNA modifications regulate the physiological…”
BackgroundYTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7
Pi, J., Wang, W., Ji, M. H., Wang, X., Wei, X., Jin, J., Liu, T., Qiang, J., Qi, Z., Li, F., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0066 · Cited by 239
Self-citationChang, S., Yim, S., & Park, H. (2019) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0230-6 · Cited by 228
Insights into N6-methyladenosine and programmed cell death in cancer
Liu, L., Li, H., Hu, D., Wang, Y., Shao, W., Zhong, J., Yang, S., Liu, J., & Zhang, J. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01508-w · Cited by 241
Self-citationMetabolic regulation of chromatin modifications and gene expression
Schvartzman, J. M., Thompson, C. B., & Finley, L. W. S. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201803061 · Cited by 233
“In nonIDH mutant leukemias, D-2HG leads to inhibition of the m6A demethylase FTO and consequent hypermethylation and destabilization of Myc transcripts (Su et al., 2018).”
BackgroundNovel insights on m6A RNA methylation in tumorigenesis: a double-edged sword
Wang, S., Chai, P., Jia, R., & Jia, R. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0847-4 · Cited by 239
Qian, J., Gao, J., Sun, X., Cao, M.-D., Shi, L., Xia, T., Zhou, W., Wang, S., Ding, Q., & Wei, J. (2019) · Oncogene · doi:10.1038/s41388-019-0861-z · Cited by 240
Targeted mRNA demethylation using an engineered dCas13b-ALKBH5 fusion protein
Li, J., Chen, Z., Chen, F., Xie, G., Ling, Y., Peng, Y., Yu, L., Luo, N., Chiang, C., & Wang, H. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa269 · Cited by 236
RNA methylation and cancer treatment
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Self-citationEpigenetics of Aging and Aging-Associated Diseases
Saul, D., & Kosinsky, R. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010401 · Cited by 247
Chen, S., Zhang, L., Li, M., Zhang, Y., Sun, M., Wang, L., Lin, J., Cui, Y., Chen, Q., Jin, C., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28913-5 · Cited by 239
RNA m6A modification and its function in diseases
Tong, J., Flavell, R. A., & Li, H.-B. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0654-8 · Cited by 233
Dynamic regulation and functions of mRNA m6A modification
Wang, S., Lv, W., Li, T., Zhang, S., Wang, H., Li, X., Wang, L., Ma, D., Zang, Y., Shen, J., et al. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02452-x · Cited by 241
Chemical Modifications in the Life of an mRNA Transcript
Nachtergaele, S., & He, C. (2018) · Annual Review of Genetics · doi:10.1146/annurev-genet-120417-031522 · Cited by 229
Self-citationExon architecture controls mRNA m 6 A suppression and gene expression
He, P. C., Wei, J., Dou, X., Harada, B. T., Zhang, Z. S., Ge, R., Liu, C., Zhang, L., Yu, X., Wang, S., et al. (2023) · Science · doi:10.1126/science.abj9090 · Cited by 229
Self-citationMa, L., Chen, T., Zhang, X., Miao, Y., Tian, X., Yu, K., Xu, X., Niu, Y., Guo, S., Zhang, C., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101801 · Cited by 223
Self-citationHuang, H., Wang, Y., Kandpal, M., Zhao, G., Cárdenas, H., Ji, Y., Chaparala, A., Tanner, E. J., Chen, J., Davuluri, R. V., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-4044 · Cited by 221
Self-citationOncometabolites in renal cancer
Yong, C., Stewart, G. D., & Frezza, C. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0210-z · Cited by 216
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“FTO expression was suppressed by R-2HG treatment in sensitive leukemia cells through downregulation of CEBPA transcription factor but not in resistant cells [30].”
BackgroundSelf-citationTargeting the RNA m6A modification for cancer immunotherapy
Li, X., Ma, S., Deng, Y., Yi, P., & Yu, J. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01558-0 · Cited by 212
FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms
Azzam, S. K., AlSafar, H. S., & Sajini, A. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073800 · Cited by 211
“Moreover, Su et al. reported that R-2HG administration resulted in synergistic interactions and displayed better therapeutic effects when combined with first-line chemotherapy drugs such as daunorubicin or decitabine, as verified in-vivo using leukemia mice models xeno-transplanted with R-2HG sensitive leukemic cells…”
BackgroundInfluentialWriters, readers and erasers of RNA modifications in cancer
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“L2-HG, rather thanD2-HG,mainly elevates in renal cell carcinoma (RCC) due to reduced expression of L2-HG dehydrogenase (L2HGDH), which can convert L2-HGback into α-KG to avoid the accumulation of L2-HG.”
BackgroundInfluentialRevisiting the role of metabolism during development
Miyazawa, H., & Aulehla, A. (2018) · Development · doi:10.1242/dev.131110 · Cited by 196
“A recent study also showed the involvement of 2-HG in regulating the epitranscriptome (i.e. the chemical modifications of RNA) by inhibiting an αKG-dependent RNA demethylase (Su et al., 2018).”
BackgroundMoonlighting functions of metabolic enzymes and metabolites in cancer
Pan, C., Li, B., & Simon, M. C. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.031 · Cited by 198
Chai, R., Wu, F., Wang, Q., Zhang, S., Zhang, K., Liu, Y., Zhao, Z., Jiang, T., Wang, Y., & Kang, C. (2019) · Aging · doi:10.18632/aging.101829 · Cited by 195
“com 1213 AGING Among the m6A RNA methylation regulators, the writers METTL3 and METTL14 were reported as suppressor genes in GBM but oncogenes in acute myelocytic leukemia (AML) and hepatocellular carcinoma [15, 26]; the reader YTHDF2 promotes cancer cell proliferation in pancreatic cancer [36]; the eraser ALKBH5 func…”
BackgroundSelf-citationQKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism
Zhao, Z., Qing, Y., Dong, L., Han, L., Wu, D., Li, Y., Li, W., Xue, J., Zhou, K., Sun, M., et al. (2023) · Cell · doi:10.1016/j.cell.2023.05.047 · Cited by 194
Self-citationm6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation
Jia, R., Chai, P., Wang, S., Sun, B., Xu, Y., Yang, Y., Ge, S., Jia, R., Yang, Y., & Fan, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1088-x · Cited by 193
“To date, structure-based selective inhibitors of the m(6)A key enzyme have been discovered [69, 70].”
BackgroundZhang, Z. S., Luo, K., Zou, Z., Qiu, M., Tian, J., Sieh, L., Shi, H., Zou, Y., Wang, G., Morrison, J., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0644-z · Cited by 192
Self-citationThe role of m6A modification in physiology and disease
Yang, C., Hu, Y., Zhou, B., Bao, Y., Li, Z., Gong, C., Yang, H., Wang, S., & Xiao, Y. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-03143-z · Cited by 200
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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