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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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.
“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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BackgroundBET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., Jacobs, H. M., Kastritis, E., Gilpatrick, T., Paranal, R. M., Qi, J., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.017 · Cited by 2,820 · cited 2× · see citing works
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BackgroundInfluentialRecurring mutations found by sequencing an acute myeloid leukemia genome
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BackgroundIDH mutation impairs histone demethylation and results in a block to cell differentiation
Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., et al. (2012) · Nature · doi:10.1038/nature10860 · Cited by 1,985 · cited 4× · see citing works
“Because IDH mutants block cell differentiation and promote tumor transformation, and inhibition of mutant IDH (IDHi) can reverse this effect, R-2HG (as the major metabolic product of IDH mutants) has been regarded as an oncometabolite (Figueroa et al., 2010; Lu et al., 2012; Rohle et al., 2013;Wang et al., 2013; Xu et…”
BackgroundResultInfluentialGlioma Groups Based on 1p/19q, IDH , and TERT Promoter Mutations in Tumors
Eckel‐Passow, J. E., Lachance, D. H., Molinaro, A. M., Walsh, K. M., Decker, P. A., Sicotte, H., Pekmezci, M., Rice, T., Kosel, M., Smirnov, I. V., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1407279 · Cited by 1,981 · cited 8× · see citing works
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“…that leukemia patients with IDH mutations tend to be more sensitive to treatment with hypomethylating agents (AZA and decitabine) (Emadi et al., 2015), ATRA (Boutzen et al., 2016), or standard chemotherapy (daunorubicin and others) (Chou et al., 2011; Patel et al., 2012), than those without.”
BackgroundResultInfluentialTranscriptional Amplification in Tumor Cells with Elevated c-Myc
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BackgroundSelf-citationFTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N 6 -Methyladenosine RNA Demethylase
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BackgroundSelf-citationAn inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells
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“Because IDH mutants block cell differentiation and promote tumor transformation, and inhibition of mutant IDH (IDHi) can reverse this effect, R-2HG (as the major metabolic product of IDH mutants) has been regarded as an oncometabolite (Figueroa et al., 2010; Lu et al., 2012; Rohle et al., 2013;Wang et al., 2013; Xu et…”
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“R-2HG has also been shown to competitively inhibit the functions of DNA and histone demethylases, such as TET2, JMJD, and KDM, leading to hypermethylated DNA and histones (Chowdhury et al., 2011; Sasaki et al., 2012).”
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Dominissini, D., Nachtergaele, S., Moshitch-Moshkovitz, S., Peer, E., Kol, N., Ben-Haim, M. S., Dai, Q., Segni, A. D., Salmon‐Divon, M., Clark, W. C., et al. (2016) · Nature · doi:10.1038/nature16998 · Cited by 1,026 · see citing works
Self-citationTargeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation
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“, 2015), and a similar trend, although still debatable (Marcucci et al., 2010), was reported in AML patients (Chou et al.”
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“…leukemia, we exposed 27 human leukemia cell lines (Table S1), none of which carries common IDH1/2 mutations (Table S2), to a series of concentrations of R-2HG; similar or even higher concentrations of R-2HGhave been used in previous studies (Fu et al., 2015; Losman et al., 2013; Lu et al., 2012).”
BackgroundResultIDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics
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“R-2HG has also been shown to competitively inhibit the functions of DNA and histone demethylases, such as TET2, JMJD, and KDM, leading to hypermethylated DNA and histones (Chowdhury et al., 2011; Sasaki et al., 2012).”
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“Two strategies of R-2HG treatment, including direct R-2HG injection and IDH1R132H-mediated generation of R-2HG, were conducted with immunodeficient NSGS (Wunderlich et al., 2010) and NRGS (Wunderlich et al., 2014) mice.”
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2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling
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“Recent studies further showed that IDH mutations and R-2HG exhibit growth-suppressive activity and glycolysis-inhibitory function 90 Cell 172, 90–105, January 11, 2018 ª 2017 Elsevier Inc. (legend on next page) Cell 172, 90–105, January 11, 2018 91 in gliomas (Bralten et al., 2011; Fu et al., 2015).”
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“…that leukemia patients with IDH mutations tend to be more sensitive to treatment with hypomethylating agents (AZA and decitabine) (Emadi et al., 2015), ATRA (Boutzen et al., 2016), or standard chemotherapy (daunorubicin and others) (Chou et al., 2011; Patel et al., 2012), than those without.”
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Self-citationIDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo
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“Recent studies further showed that IDH mutations and R-2HG exhibit growth-suppressive activity and glycolysis-inhibitory function 90 Cell 172, 90–105, January 11, 2018 ª 2017 Elsevier Inc. (legend on next page) Cell 172, 90–105, January 11, 2018 91 in gliomas (Bralten et al., 2011; Fu et al., 2015).”
BackgroundAML cells are differentially sensitive to chemotherapy treatment in a human xenograft model
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Self-citationHematopoietic differentiation is required for initiation of acute myeloid leukemia
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“R-2HG also causes downregulation of FTO expression indirectly through epigenetic suppression of CEBPA, an essential hematopoiesis-related transcription factor that is required for leukemogenesis (Ohlsson et al., 2014; Ye et al., 2015), via an m(6)A-dependent mechanism in which accumulation of internal m(6)A causes red…”
BackgroundBoutzen, H., Saland, E., Larrue, C., de Toni, F., Gales, L., Castelli, F. A., Cathebas, M., Zaghdoudi, S., Stuani, L., Kaoma, T., et al. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20150736 · Cited by 86 · cited 4× · see citing works
“…that leukemia patients with IDH mutations tend to be more sensitive to treatment with hypomethylating agents (AZA and decitabine) (Emadi et al., 2015), ATRA (Boutzen et al., 2016), or standard chemotherapy (daunorubicin and others) (Chou et al., 2011; Patel et al., 2012), than those without.”
BackgroundInfluentialEmadi, A., Faramand, R. G., Carter‐Cooper, B., Tolu, S. S., Ford, L. A., Lapidus, R. G., Wetzler, M., Wang, E. S., Etemadi, A., & Griffiths, E. A. (2015) · American Journal of Hematology · doi:10.1002/ajh.23965 · Cited by 78 · cited 4× · see citing works
“…it was reported that leukemia patients with IDH mutations tend to be more sensitive to treatment with hypomethylating agents (AZA and decitabine) (Emadi et al., 2015), ATRA (Boutzen et al., 2016), or standard chemotherapy (daunorubicin and others) (Chou et al., 2011; Patel et al., 2012), than…”
BackgroundInfluentialIDH Mutation, Competitive Inhibition of FTO, and RNA Methylation
Elkashef, S. M., Lin, A.-P., Myers, J., Sill, H., Jiang, D., Dahia, P. L. M., & Aguiar, R. C. T. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.04.001 · Cited by 78 · cited 1× · see citing works
“Based on our previous study on FTO in AML, a recent study suggested that R-2HGmay target FTO (Elkashef et al., 2017).”
Wunderlich, M., Brooks, R. A., Panchal, R., Rhyasen, G. W., Danet-Desnoyers, G. A., & Mulloy, J. C. (2014) · Blood · doi:10.1182/blood-2014-02-556340 · Cited by 72 · cited 4× · see citing works
“R-2HG treatment led to a substantial decrease of leukemic blasts in PB from both NSGS and NRGS mice with these sensitive cells, but not with the 2HG-resistant AML cells (Figure 1L).”
MethodInfluentialSelf-citationInitiation of MLL-rearranged AML is dependent on C/EBPα
Ohlsson, E., Hasemann, M. S., Willer, A., Lauridsen, F. K. B., Rapin, N., Jendholm, J., & Porse, B. T. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20130932 · Cited by 67 · cited 2× · see citing works
“R-2HG also causes downregulation of FTO expression indirectly through epigenetic suppression of CEBPA, an essential hematopoiesis-related transcription factor that is required for leukemogenesis (Ohlsson et al., 2014; Ye et al., 2015), via an m(6)A-dependent mechanism in which accumulation of internal m(6)A causes red…”
BackgroundWang, J., Dong, D.-F., Wang, M., & Gao, K. (2014) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2014.15.1.427 · Cited by 48 · cited 3× · see citing works
“Knockdown of YTHDF2, a major m6A reader that is responsible for the decay of m6A-modified mRNA transcripts (Wang et al., 2014b) and that is known to bind MYC mRNA (Figure S4N), noticeably increased the stability and expression of MYC transcripts in leukemia cells (Figures 4J and S4O).”
BackgroundResultHodge, R. (1998) · Humana Press eBooks · doi:10.1385/0-89603-494-1:73 · Cited by 5 · see citing works
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BackgroundInfluentialSelf-citationDynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism
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BackgroundInfluentialThe hallmarks of cancer metabolism: still emerging
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Functions of N6-methyladenosine and its role in cancer
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“As a metabolite by mutant IDH1/2 enzymes, R-2hydroxyglutarate (R-2HG) elevates m6A level and enhances the YTHDF2-mediated-degradation of MYC, ASB2, and RARA [160].”
BackgroundRole of RNA modifications in cancer
Barbieri, I., & Kouzarides, T. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0253-2 · Cited by 1,322 · see citing works
RNA modifications modulate gene expression during development
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“Inhibition of FTO reduces AML cell proliferation and viability in these cell types ( 59, 60 ).”
Self-citationm6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer
Huang, H., Weng, H., & Chen, J. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.02.004 · Cited by 1,238 · see citing works
Self-citationThe role of m6A RNA methylation in human cancer
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The potential role of RNA N6-methyladenosine in Cancer progression
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“In addition, some researchers have focused on targeted cancer therapies related to m6A, such as treatment with R-2HG to increase m6A mRNA modification in R-2HG-sensitive leukemia cells by inhibiting FTO activity, thus generating antileukemia effects [151].”
BackgroundWeng, H., Huang, H., Wu, H., Qin, X., Zhao, B. S., Dong, L., Shi, H., Skibbe, J. R., Shen, C., Hu, C., et al. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.11.016 · Cited by 974 · see citing works
“Interestingly, while METTL14 promotes stability ofMYCmRNA through affecting m(6)A abundance mainly on the 30-terminal exon, we very recently show that FTO also promotes stability of MYC mRNA through inhibition of YTHDF2mediated RNA decay attributed to decreased m(6)A abundance on the 50-terminal and internal exons of…”
BackgroundSelf-citationThe role of m6A RNA methylation in cancer
Sun, T., Wu, R., & Ming, L. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.108613 · Cited by 969 · see citing works
Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia
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“any further significant fold changes of these hyper peaks in MONOMAC6 AML cells (Figures 6E and 6F), which is consistent with reported observations in AML cells with FTO KD or R-2HG treatment (Su et al., 2018).”
BackgroundResultInfluentialSelf-citationRNA N6-methyladenosine modification in cancers: current status and perspectives
Deng, X., Su, R. J., Weng, H., Huang, H., Li, Z., & Chen, J. (2018) · Cell Research · doi:10.1038/s41422-018-0034-6 · Cited by 848 · see citing works
“cell-cycle arrest and apoptosis in a time- and dose-dependent manner in the vast majority of the tested samples.(69) Exogenous R2HG treatment showed no noticeable inhibitory effects on viability/proliferation of IDH-mutant AML cells, indicating these cells can tolerate the potential inhibitory effect of R-2HG.”
BackgroundResultInfluentialSelf-citationm6A RNA methylation: from mechanisms to therapeutic potential
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“FTO is upregulated in a subset of AML and plays oncogenic roles (Li et al , 2017c; Su et al , 2018), including the gain of resistance to tyrosine kinase inhibitor therapy (Yan et al , 2018).”
Self-citationDifferential m6A, m6Am, and m1A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm
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“Other types of tumors could exploit aberrant RNA methylation to gain survival and growth advantages via AKT activation in addition to other proposed mechanisms 24–35 .”
Self-citationTargeting FTO suppresses cancer stem cell maintenance and immune evasion
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“Western blot assay was performed as described previously (Su et al., 2018).”
InfluentialSelf-citationm6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade
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Self-citationThe Critical Role of RNA m6A Methylation in Cancer
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Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally
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Self-citationThe interplay between m6A RNA methylation and noncoding RNA in cancer
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“IGF2BP1 Ovarian and Liver cancer Oncogene Promoting tumor cell growth and cell invasion Enhancing SRF mRNA stability in an m6A-dependent manner [59] Ma et al.”
BackgroundFTO-Dependent N 6 -Methyladenosine Regulates Cardiac Function During Remodeling and Repair
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Self-citationThe roles of DNA, RNA and histone methylation in ageing and cancer
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Self-citationStem cell programs in cancer initiation, progression, and therapy resistance
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“Genetic ablation of the ubiquitin ligase FBXW7, a negative regulator of MYC, forces quiescent LSCs to re-enter the cell cycle and increases their sensitivity to the tyrosine kinase inhibitor (TKI) imatinib [331].”
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“2017), andm(6)Amodification was also shown to exert anti-leukemic activity in recent studies (Li et al. 2017b; Su et al. 2018).”
BackgroundSuppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
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The evolving metabolic landscape of chromatin biology and epigenetics
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The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities
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“In a seminal study, Su R et al. FTO was found to be inhibited by the oncometabolite R-2-hydroxyglutarate (R-2HG) [37].”
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“m6A writers (16-18) and m6A erasers (19-21) are differentially”
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“Recent studies have reported a causal role of m6A-RNA methylation in maintaining tumorigenesis and stem-like characteristics of glioblastoma cells and other cancers (Barbieri et al., 2017; Han et al., 2019; Li et al., 2017b; Liu et al., 2018; Su et al., 2018; Vu et al., 2017; Zhang et al., 2017).”
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The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8
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Self-citationm6A-dependent glycolysis enhances colorectal cancer progression
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Link Between m6A Modification and Cancers
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The roles and implications of RNA m6A modification in cancer
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Self-citationm6A modification: recent advances, anticancer targeted drug discovery and beyond
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Self-citationTumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance
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RNA modifications regulating cell fate in cancer
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YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma
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“The demethylase FTO (fat mass-and obesity-associated protein) decreases global m(6)A levels, leading to either downregulation of tumor suppressor genes or upregulation of tumor promoter genes [4, 5].”
BackgroundSelf-citationMapping the epigenetic modifications of DNA and RNA
Zhao, L.-Y., Song, J., Liu, Y., Song, C., & Yi, C. (2020) · Protein & Cell · doi:10.1007/s13238-020-00733-7 · Cited by 366 · see citing works
Biological roles of adenine methylation in RNA
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METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis
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Self-citationRole of m6A RNA methylation in cardiovascular disease (Review)
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N6-methyladenosine regulates glycolysis of cancer cells through PDK4
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m6A-binding proteins: the emerging crucial performers in epigenetics
Zhao, Y., Shi, Y., Shen, H., & Xie, W. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00872-8 · Cited by 317 · see citing works
“Paris and colleagues observed that YTHDF2 was overexpressed in AML and closely correlated with LSCs activity [81].”
BackgroundInfluentialMultiple functions of m6A RNA methylation in cancer
Pan, Y., Ma, P., Liu, Y., Li, W., & Shu, Y. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0590-8 · Cited by 313 · see citing works
“Oncogene AML Promote tumorigenesis Stabilize MYC and CEBPA [47]”
BackgroundInfluentialIdentification of differential RNA modifications from nanopore direct RNA sequencing with xPore
Pratanwanich, P. N., Yao, F., Chen, Y., Koh, C. W. Q., Wan, Y. K., Hendra, C., Poon, P. S. Y., Goh, Y. T., Yap, P. M. L., Chooi, J.-Y., et al. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-00949-w · Cited by 299 · see citing works
The Biogenesis and Precise Control of RNA m6A Methylation
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FTO mediates LINE1 m 6 A demethylation and chromatin regulation in mESCs and mouse development
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Self-citationm6A RNA modifications are measured at single-base resolution across the mammalian transcriptome
Hu, L., Liu, S., Peng, Y., Ge, R., Su, R. J., Senevirathne, C., Harada, B. T., Dai, Q., Wei, J., Zhang, L., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01243-z · Cited by 278 · see citing works
Self-citationMechanism of RNA modification N6-methyladenosine in human cancer
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 · see citing works
“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 270 · see citing works
RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential
Qu, J., Yan, H., Hou, Y., Cao, W., Liu, Y., Zhang, E., He, J., & Cai, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01224-4 · Cited by 264 · see citing works
RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer
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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 261 · see citing works
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 · see citing works
“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 254 · see citing works
“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 · see citing works
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“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 249 · see citing works
“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 · see citing works
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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 218 · see citing works
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 · see citing works
“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 · see citing works
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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 238 · see citing works
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 241 · see citing works
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RNA m6A modification and its function in diseases
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Dynamic regulation and functions of mRNA m6A modification
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Chemical Modifications in the Life of an mRNA Transcript
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Self-citationExon architecture controls mRNA m 6 A suppression and gene expression
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Self-citationOncometabolites in renal cancer
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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
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“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…”
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“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).”
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“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…”
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Self-citationm6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation
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“To date, structure-based selective inhibitors of the m(6)A key enzyme have been discovered [69, 70].”
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- 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 · 2017: 1
- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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