The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
The Cancer Genome Atlas Research Network (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1301689 · Cited by 5,078 · cited 1×
“To address this question, we conducted integrative analysis of the TCGA AML microarray dataset (Ley et al., 2013) with our RNA-seq data shown in Figure 2A.”
MethodN6-methyladenosine-dependent regulation of messenger RNA stability
Wang, X., Lu, Z., Gomez, A., Hon, G. C., Yue, Y., Han, D., Fu, Y., Parisien, M., Dai, Q., Jia, G., et al. (2014) · Nature · doi:10.1038/nature12730 · Cited by 4,558 · cited 3×
“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).”
BackgroundResultSelf-citationGenomic classification and prognosis in acute myeloid leukemia
Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V. I., Paschka, P., Roberts, N. D., Potter, N. E., Heuser, M., Thol, F., Bolli, N., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1516192 · Cited by 4,350 · cited 7×
“80% of grade II-III gliomas and secondary glioblastoma (GBM), 10%–20% of acute myeloid leukemia (AML) patients, and at a lower rate in other cancers; most of these lesions involve mutations of arginine (R) residues in codon 132 for IDH1 (IDH1R132) and residues 140 and 172 for IDH2 (IDH2R140 and IDH2R172) (Brat et al.,…”
BackgroundInfluentialCancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO
Jia, G., Fu, Y., Zhao, X., Dai, Q., Zheng, G., Yang, Y., Yi, C., Lindahl, T., Pan, T., Yang, Y.-G., et al. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.687 · Cited by 4,106
Self-citationA METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation
Liu, J., Yue, Y., Han, D., Wang, X., Fu, Y., Zhang, L., Jia, G., Yu, M., Lu, Z., Deng, X., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1432 · Cited by 3,433
Self-citationComprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas
The Cancer Genome Atlas Research Network (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1402121 · Cited by 3,148
BET 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 2,888 · cited 2×
“Primary AML cells with IDH mutations are also sensitive to JQ1, an inhibitor of MYC signaling (Delmore et al., 2011), often with an IC50 lower than 1 mM, thoughwith a higher IC50 than AML cells with wild-type IDH (Figure 7B; Table S4), likely due to the hyper-activation of MYC signaling in the former.”
BackgroundSelf-citationXu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · cited 3×
“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…”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–200 of 1,000
Li, B., Jiang, J., Assaraf, Y. G., Xiao, H., Chen, Z., & Huang, C. (2020) · Drug Resistance Updates · doi:10.1016/j.drup.2020.100720 · Cited by 190
Role of main RNA modifications in cancer: N6-methyladenosine, 5-methylcytosine, and pseudouridine
Xue, C., Chu, Q., Zheng, Q., Jiang, S., Bao, Z., Su, Y., Lü, J., & Li, L. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01003-0 · Cited by 192
Han, H., Gao, F., Song, S., Jiang, Y., Qian, C., Zhang, W., Su, Q., Xue, X., Zhuang, W., & Li, B.-Z. (2020) · Blood · doi:10.1182/blood.2019003764 · Cited by 181
RNA-binding proteins in regulating mRNA stability and translation: roles and mechanisms in cancer
Li, W., Deng, X., & Chen, J. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.03.025 · Cited by 189
Self-citationThe RNA N6-methyladenosine modification landscape of human fetal tissues
Xiao, S., Cao, S., Huang, Q., Xia, L., Deng, M., Yang, M., Jia, G., Liu, X., Shi, J., Wang, W., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0315-4 · Cited by 180
Self-citationThe FTO/miR‐181b‐3p/ARL5B signaling pathway regulates cell migration and invasion in breast cancer
Xu, Y., Ye, S., Zhang, N., Zheng, S., Liu, H., Zhou, K., Wang, L., Cao, Y., Sun, P., & Wang, T. (2020) · 癌症：英文版 · doi:10.1002/cac2.12075 · Cited by 180
“[28] discovered that R-2hydroxyglutarate exerted antitumor activity by targeting the FTO/m6A/MYC/CEBPA signaling pathway, leading to suppressed proliferation or survival of leukemia and glioma cells expressing high levels of FTO.”
BackgroundChai, R., Chang, Y., Chang, X., Pang, B., An, S. Y., Zhang, K., Chang, Y., Jiang, T., & Wang, Y. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01124-z · Cited by 176
“IDH mutation can inhibit the activity of m6A ‘eraser’ FTO in leukemia and glioma cells by producing R-2-hydroxyglutarate [35, 36].”
BackgroundSelf-citationRNA modification: mechanisms and therapeutic targets
Qiu, L., Qian, J., Li, Y., & Han, J. (2023) · Molecular Biomedicine · doi:10.1186/s43556-023-00139-x · Cited by 182
Wang, W., Shao, F., Yang, X., Wang, J., Zhu, R., Yang, Y., Zhao, G., Guo, D. S., Sun, Y., Wang, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23501-5 · Cited by 174
Liu, W.-W., Zheng, S.-Q., Tian, L., Fei, Y.-F., Wang, C., Zhang, S., Wang, F., Jiang, G., & Wang, H. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01777-5 · Cited by 187
“412 Moreover, the feasibility of administrating m6A regulators inhibitors to improve immunotherapy effectiveness needs further investigation.”
BackgroundEpitranscriptomics in liver disease: Basic concepts and therapeutic potential
Zhao, Z., Meng, J., Su, R. J., Zhang, J., Chen, J., Ma, X., & Xia, Q. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.04.009 · Cited by 166
Self-citationm6A-RNA Demethylase FTO Inhibitors Impair Self-Renewal in Glioblastoma Stem Cells
Huff, S. E., Tiwari, S. K., Gonzalez, G. M., Wang, Y., & Rana, T. M. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.0c00841 · Cited by 173
“36 Recently, a new derivative of meclofenamic acid (MA) called FB23–2 was also shown to suppress proliferation and promote differentiation in AML cells and prolong survival in AML mouse models.”
Self-citationN 1 -methyladenosine modification in cancer biology: Current status and future perspectives
Li, J., Zhang, H., & Wang, H. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.11.045 · Cited by 170
“R-2HG Suppress FTO activity AML, GBM: Inhibit proliferation/survival of FTO-high cancer cells [97]”
BackgroundThe Biology of m6A RNA Methylation in Normal and Malignant Hematopoiesis
Vu, L., Cheng, Y., & Kharas, M. G. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0959 · Cited by 168
Tommasini-Ghelfi, S., Murnan, K., Kouri, F. M., Mahajan, A., May, J., & Stegh, A. H. (2019) · Science Advances · doi:10.1126/sciadv.aaw4543 · Cited by 166
FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell
Relier, S., Ripoll, J., Guillorit, H., Amalric, A., Achour, C., Boissière‐Michot, F., Vialaret, J., Attina, A., Debart, F., Choquet, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21758-4 · Cited by 168
FTO – A Common Genetic Basis for Obesity and Cancer
Lan, N., Lu, Y., Zhang, Y., Pu, S., Xi, H., Nie, X., Liu, J., & Yuan, W. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.559138 · Cited by 176
“Unknown Su et al., 2018 CS1/CS2 Direct interaction between CS1/CS2 and intracellular FTO protein inhibits its demethylase activity.”
BackgroundThe proteins of mRNA modification: writers, readers, and erasers
Flamand, M. N., Tegowski, M., & Meyer, K. D. (2023) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052521-035330 · Cited by 164
METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism
Han, L., Dong, L., Leung, K., Zhao, Z., Li, Y.-C., Gao, L., Chen, Z.-H., Xue, J., Qing, Y., Li, W., et al. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2022.12.006 · Cited by 152
Self-citationMetabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases
Baksh, S. C., & Finley, L. W. S. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.09.010 · Cited by 165
“2HG suppresses FTO activity in leukemia cells, leading to decreased expression of the lineage TF CCAAT enhancer binding protein α (C/ EBPα) that enforces normal HSC quiescence and myeloid differentiation [29,30].”
Backgroundm6A modification in RNA: biogenesis, functions and roles in gliomas
Zhang, Y., Geng, X., Li, Q., Xu, J., Tan, Y., Xiao, M., Song, J., Liu, F., Fang, C., & Wang, H. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01706-8 · Cited by 163
RNA methylations in human cancers
Han, X., Wang, M., Zhao, Y., Yang, Y., & Yang, Y. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.11.007 · Cited by 159
Changes of N6-methyladenosine modulators promote breast cancer progression
Wu, L., Wu, D., Ning, J., Liu, W., & Zhang, D. (2019) · BMC Cancer · doi:10.1186/s12885-019-5538-z · Cited by 162
“For m6A demethylases, previous studies have suggested that FTO has an oncogenic role in acute myeloid leukemia [16, 17].”
N6-methyladenosine and Neurological Diseases
Zhang, N., Ding, C., Zuo, Y., Peng, Y., & Zuo, L. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02739-0 · Cited by 160
Yang, X., Shao, F., Guo, D. S., Wang, W., Wang, J., Zhu, R., Gao, Y., He, J., & Lu, Z. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03739-z · Cited by 159
RNA-modifying proteins as anticancer drug targets
Boriack‐Sjodin, P. A., Ribich, S. A., & Copeland, R. A. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.71 · Cited by 157
The Roles of 2-Hydroxyglutarate
Du, X., & Hu, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.651317 · Cited by 160
Song, T., Yang, Y., Wei, H., Xie, X., Lü, J., Zeng, Q., Peng, J., Zhou, Y., Jiang, S., & Peng, J. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz312 · Cited by 152
“Interestingly, it was observed high m6A modification of FTO mRNA itself after Zfp217 knockout through MeRIP-seq as well, implying a feedback mechanism of which high m6A modification of FTO mRNA inhibits FTO expression itself (32).”
BackgroundMethodInfluentialThe RNA m6A writer WTAP in diseases: structure, roles, and mechanisms
Huang, Q., Mo, J., Liao, Z., Chen, X., & Zhang, B. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05268-9 · Cited by 156
Self-citationN6-methyladenosine-mediated gene regulation and therapeutic implications
Liu, Y., Yang, D., Liu, T., Chen, J., Yu, J., & Yi, P. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.03.005 · Cited by 152
Self-citationMETTL3/YTHDF2 m 6 A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer
Xie, H., Li, J., Ying, Y., Yan, H., Jin, K., Ma, X., He, L., Xu, X., Liu, B., Wang, X., et al. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15063 · Cited by 148
Chang, Y., Chai, R., Pang, B., Chang, X., An, S. Y., Zhang, K., Jiang, T., & Wang, Y. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.04.020 · Cited by 148
Self-citationTrans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity
Fan, H., Xia, S., Xiang, J., Li, Y., Ross, M. O., Lim, S. A., Yang, F., Tu, J., Xie, L., Dougherty, U., et al. (2023) · Nature · doi:10.1038/s41586-023-06749-3 · Cited by 150
Self-citationYue, C., Chen, J., Li, L., Li, L., Chen, J., & Guo, Y.-M. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01731-7 · Cited by 143
“Consistently, this mechanism has been proposed in another study that FTO mediates m6A modification to accelerate the expression of MYC [37].”
BackgroundSelf-citationm6A RNA modification controls autophagy through upregulating ULK1 protein abundance
Jin, S., Zhang, X., Miao, Y., Liang, P., Zhu, K., She, Y., Wu, Y., Liu, D.-A., Huang, J., Ren, J., et al. (2018) · Cell Research · doi:10.1038/s41422-018-0069-8 · Cited by 130
Critical Enzymatic Functions of FTO in Obesity and Cancer
Deng, X., Su, R. J., Stanford, S., & Chen, J. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00396 · Cited by 143
“MA has been further proved to effectively inhibit the survival and growth of GBM cells through suppression of the m6A demethylase activity of FTO (32).”
BackgroundInfluentialSelf-citationmRNA Regulation by RNA Modifications
Gilbert, W. V., & Nachtergaele, S. (2023) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052521-035949 · Cited by 144
“Similarly, m 6 A has also been shown to destabilize oncogenes in multiple cancers (105, 106), so this interplay between stabilizing and destabilizing modifications could be a more generally applicable mechanism in other biological contexts.”
BackgroundSelf-citationControl of endothelial quiescence by FOXO-regulated metabolites
Andrade, J., Shi, C., Costa, A. S. H., Choi, J., Kim, J., Doddaballapur, A., Sugino, T., Ong, Y. T., Castro, M., Zimmermann, B., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00637-6 · Cited by 133
METTL3 regulates WTAP protein homeostasis
Sorci, M., Ianniello, Z., Cruciani, S., Larivera, S., Ginistrelli, L. C., Capuano, E., Marchioni, M., Fazi, F., & Fatica, A. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0843-z · Cited by 136
Function and evolution of RNA N6-methyladenosine modification
Zhu, Z., Huo, F., & Pei, D. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.45231 · Cited by 136
“In addition, R-2-hydroxyglutarate (R-2HG) can obviate FTO activity, which augments the m6A modification in R-2HG-sensitive leukemic cells, and then reduce the stability of MYC/CEBPA transcripts, promoting cell cycle arrest and apoptosis [131].”
BackgroundPrinciples of RNA methylation and their implications for biology and medicine
Zhou, Y., Kong, Y., Fan, W., Tao, T., Xiao, Q., Li, N., & Zhu, X. M. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110731 · Cited by 134
Aberrant expression of enzymes regulating m6A mRNA methylation: implication in cancer
Pinello, N., Stephanie, S., & Justin, J.-L. W. (2018) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2018.0365 · Cited by 132
Li, X., Li, X., Mu, Z., Zhou, J., Zhou, P., Xie, C., & Jiang, S. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0132 · Cited by 133
“downstreampathway in leukemia (22), andQi and colleagues indicates that knockdown of FTO inhibits glioblastoma stem cell (GSC) growth and self-renewal (23).”
BackgroundXu, F., Li, J., Ni, M., Cheng, J., Zhao, H., Wang, S., Zhou, X. Y., & Wu, X. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01340-8 · Cited by 133
“It has been shown that YTHDF2 targets a plethora of mRNAs for degradation in cancers, such as, TNFR2, cMyc and CEBPA in leukemia [26, 27], EGFR, IL11, SERP INE2 and SOCS2 in liver cancer [28, 29, 39], and PD-1, CXCR4, and SOX10 in melanoma [33].”
BackgroundExosomes of pasteurized milk: potential pathogens of Western diseases
Melnik, B. C., & Schmitz, G. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-018-1760-8 · Cited by 134
N6-methyladenosine modification of MALAT1 promotes metastasis via reshaping nuclear speckles
Wang, X., Liu, C., Zhang, S., Yan, H., Zhang, L., Jiang, A., Liu, Y., Feng, Y., Li, D., Guo, Y., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.01.015 · Cited by 132
The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability
Zhang, N., Shen, Y., Li, H., Chen, Y., Zhang, P., Lou, S., & Deng, J. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00735-x · Cited by 130
PRMT5 regulates RNA m6A demethylation for doxorubicin sensitivity in breast cancer
Wu, Y., Wang, Z., Han, L., Guo, Z., Yan, B., Guo, L., Zhao, H., Wei, M., Hou, N., Ye, J., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.03.003 · Cited by 127
Self-citationm6A-regulated tumor glycolysis: new advances in epigenetics and metabolism
Yue, S., Liu, H., Su, H.-F., Luo, C., Liang, H., Zhang, B., & Zhang, W. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01841-8 · Cited by 137
“There is an urgent need to identify specific inhibitors that have strong anti-tumor efficacy, high bioavailability and few drug-related side effects in order to be applied in clinic as soon as possible [71, 200, 208, 209].”
BackgroundSelf-citationSchiff, D., van den Bent, M. J., Vogelbaum, M. A., Wick, W., Miller, C. R., TAPHOORN, M. J. B., Pope, W. B., Brown, P. D., Platten, M., Jalali, R., et al. (2019) · Neuro-Oncology · doi:10.1093/neuonc/noz033 · Cited by 125
Rong, Z., Li, Z., He, J., Liu, L.-Y. D., Ren, X.-X., Gao, J., Mu, Y., Guan, Y., Duan, Y., Zhang, X., et al. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00369 · Cited by 126
METTL3 Promotes the Progression of Gastric Cancer via Targeting the MYC Pathway
Yang, D.-D., Chen, Z., Yu, K., Lu, J., Wu, Q.-N., Wang, Y., Ju, H., Xu, R., Liu, Z., & Zeng, Z.-L. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00115 · Cited by 126
Self-citationNovel positioning from obesity to cancer: FTO, an m6A RNA demethylase, regulates tumour progression
Chen, J., & Du, B. (2018) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-018-2796-0 · Cited by 126
Self-citationRNA methylation in mammalian development and cancer
Song, P., Tayier, S., Cai, Z., & Jia, G. (2021) · Cell Biology and Toxicology · doi:10.1007/s10565-021-09627-8 · Cited by 125
Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets
Miranda‐Gonçalves, V., Lameirinhas, A., Henrique, R., & Jerónimo, C. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00427 · Cited by 125
A dynamic reversible RNA N6‐methyladenosine modification: current status and perspectives
Bi, Z., Liu, Y., Zhao, Y., Yao, Y., Wu, R., Liu, Q., Wang, Y., & Wang, X. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28014 · Cited by 121
Self-citationWriters, readers, and erasers RNA modifications and drug resistance in cancer
Chen, D., Gu, X., Nurzat, Y., Xu, L., Li, X., Wu, L., Jiao, H., Gao, P., Zhu, X., Yan, D., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02089-6 · Cited by 127
“…R-2HG, in conjunction with first-line chemo-therapeutic drugs such as ATRA, AZA, decitabine, and ADR, synergistically induces cell cycle arrest and apoptosis in leukemia and glioma cells, underscoring the efficacy of targeting RNA modification regulators in cancer treatment strategies [342].”
BackgroundMethyltransferase-like proteins in cancer biology and potential therapeutic targeting
Qi, Y., Liu, Z., Hong, L., Li, P., & Ling, Z. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01477-7 · Cited by 127
The Emerging Roles of RNA Modifications in Glioblastoma
Dong, Z., & Cui, H. (2020) · Cancers · doi:10.3390/cancers12030736 · Cited by 123
“Other studies also show that FTO functions as an oncogenic role via maintaining the stability of transcripts of avian myelocytomatosis viral oncogene homolog (c-Myc) and CCAAT enhancer binding protein alpha (CEBPA) in glioma, especially IDH1/2 mutant glioma [64].”
BackgroundALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing
Zhang, L., Xiong, Q., Perez, S. P., Liu, C., Wei, J., Le, C., Zhang, L., Harada, B. T., Dai, Q., Feng, X., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00709-7 · Cited by 121
Self-citationChen, Y., Lu, Z., Qi, C., Yu, C., Li, Y., Wang, H., Wang, R., Luo, W., Shen, D., Ding, L., et al. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01549-1 · Cited by 121
Epigenetic modulations of noncoding RNA: a novel dimension of Cancer biology
Yang, X. F., Liu, M., Li, M., Zhang, S., Hiju, H., Sun, J. P., Mao, Z., Zheng, M., & Feng, B. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01159-9 · Cited by 119
“Recent study found that R-2HG inhibited FTO activity, thereby increasing global m6A level, which in turn decreased the stability of MYC and suppressed leukemia progression both in vitro and in vivo [126].”
BackgroundRNA m6A Modification in Cancers: Molecular Mechanisms and Potential Clinical Applications
Gu, C., Shi, X., Dai, C., Shen, F., Rocco, G., Chen, J., Huang, Z., Chen, C., He, C., Huang, T., et al. (2020) · The Innovation · doi:10.1016/j.xinn.2020.100066 · Cited by 119
Self-citationZhang, X., Wang, Y., Zhao, H., Han, X., Zhao, T., Qu, P., Li, G., & Wang, W. (2020) · Stem Cell Research & Therapy · doi:10.1186/s13287-020-01707-6 · Cited by 114
Self-citationTsuchiya, K., Yoshimura, K., Inoue, Y., Iwashita, Y., Yamada, H., Kawase, A., Watanabe, T., Tanahashi, M., Ogawa, H., Funai, K., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1962656 · Cited by 114
“On the other hand, YTHDF2 also has an antitumor effect in leukemic cells via the attenuation of the stability of MYC and CEBPA transcripts.(21) Given these inconsistent findings, we can say it is still controversial as to how these m6A reader proteins, YTHDF1 and YTHDF2, affect oncogenic or anti-oncogenic function in…”
BackgroundLiu, B., Zhou, J., Wang, C., Chi, Y., Wei, Q., Fu, Z., Lian, C., Huang, Q., Liao, C., Yang, Z., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2540-y · Cited by 113
TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal
Li, Y., Xue, M., Deng, X., Dong, L., Nguyen, L. X. T., Ren, L., Han, L., Li, C., Xue, J., Zhao, Z., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.07.001 · Cited by 115
Self-citationQiao, K., Liu, Y., Xu, Z., Zhang, H., Zhang, H., Zhang, C., Chang, Z., Lu, X., Li, Z., Luo, C., et al. (2020) · Angiogenesis · doi:10.1007/s10456-020-09744-8 · Cited by 111
“In addition, m6A was related to many cancer types, including lung cancer [32], leukemia [33, 34], colon cancer [35, 36], gastric cancer [37], glioma [38], bladder cancer [39], nasopharyngeal cancer [40].”
BackgroundXiao, Y., Thakkar, K. N., Zhao, H., Broughton, J. P., Li, Y., Seoane, J. A., Diep, A. N., Metzner, T. J., von Eyben, R., Dill, D. L., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2000516117 · Cited by 118
Wang, Y., Wild, A. T., Turcan, Ş., Wu, W., Sigel, C., Klimstra, D. S., Ma, X., Gong, Y., Holland, E. C., Huse, J. T., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaz3221 · Cited by 109
Self-citationmTORC1 promotes cell growth via m6A-dependent mRNA degradation
Cho, S., Lee, G., Pickering, B. F., Jang, C., Park, J. H., He, L., Mathur, L., Kim, S.-S., Jung, S., Tang, H.-W., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.010 · Cited by 113
Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m6A signaling
Sun, K., Du, Y., Hou, Y., Zhao, M., Li, J., Du, Y., Zhang, L., Chen, C., Yang, H., Yan, F., et al. (2021) · Theranostics · doi:10.7150/thno.55574 · Cited by 109
“In addition, R-2HG also inhibits FTO activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells [21].”
BackgroundSelf-citationWang, K., Zhou, L., Liu, F., Liang, L., Ju, J., Tian, P.-C., Liu, C.-Y., Li, X., Chen, X., Wang, T., et al. (2022) · Advanced Science · doi:10.1002/advs.202106058 · Cited by 109
METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions
Li, Y., He, X., Xiao, L., Gong, Z., Li, Q., Zhang, L., Yang, R., Wu, C., Huang, J., Ding, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34209-5 · Cited by 120
Self-citationZhang, F., Liu, H., Duan, M., Wang, G., Zhang, Z., Wang, Y., Qian, Y., Yang, Z., & Jiang, X. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01304-5 · Cited by 111
Self-citationCao, X., Geng, Q., Fan, D., Wang, Q., Wang, X., Zhang, M., Zhao, L., Jiao, Y., Deng, T., Liu, H., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-022-01704-8 · Cited by 115
Liu, X., Gonzalez, G. M., Dai, X., Miao, W., Yuan, J. J., Huang, M., Bade, D., Li, L., Sun, Y., & Wang, Y. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.09.007 · Cited by 105
Self-citationYuan, Y., Du, Y., Wang, L., & Liu, X. (2020) · Journal of Cancer · doi:10.7150/jca.42338 · Cited by 106
“Corresponded to the detected abnormal m6A modification of MYC mRNA in many cancers, including myeloid leukemia [15], bladder cancer [16], and GBM [29], aberrant MYC expression was also caused by METTL3–mediated m6A modification in PCa.”
BackgroundStructural Insights into N 6 -Methyladenosine (m 6 A) Modification in the Transcriptome
Huang, J. B., & Yin, P. (2018) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2018.03.001 · Cited by 107
“FTO, which is found in both nucleus and cytoplasm [90], has been reported to regulate mRNA splicing, gene expression, and cell differentiation [34,56,91,92].”
BackgroundZhao, Y., Chen, Y., JIN, M. L., & Wang, J. (2021) · Theranostics · doi:10.7150/thno.54967 · Cited by 106
Level of N6-Methyladenosine in Peripheral Blood RNA: A Novel Predictive Biomarker for Gastric Cancer
Ge, L., Zhang, N., Chen, Z., Song, J., Wu, Y., Li, Z., Chen, F., Wu, J., Li, D., Li, J., et al. (2020) · Clinical Chemistry · doi:10.1093/clinchem/hvz004 · Cited by 102
Xie, G., Wu, X.-N., Ling, Y., Rui, Y., Wu, D., Zhou, J., Li, J., Lin, S., Peng, Q., Li, Z., et al. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.08.028 · Cited by 102
Roles of RNA Modifications in Diverse Cellular Functions
Wilkinson, E., Cui, Y., & He, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.828683 · Cited by 109
Liu, L., Liu, X., Dong, Z., Li, J., Yu, Y. H., Chen, X., Ren, F., Cui, G., & Sun, R. (2019) · Journal of Cancer · doi:10.7150/jca.35053 · Cited by 101
“Increased expression of FTO in leukaemia was believed to be associated with sensitivity to the chemotherapy drug R-2HG [40].”
BackgroundWang, L.-C., Chen, S.-H., Shen, X., Li, D., Liu, H., Ji, Y.-L., Li, M., Yu, K., Yang, H. M., Chen, J., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.536875 · Cited by 102
Self-citationYao, X., Li, W., Li, L., Li, M., Zhao, Y., Fang, D., Zeng, X., & Luo, Z. Y. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04711-1 · Cited by 101
Xu, Y., Zhou, J., Li, L., Yang, W., Zhang, Z., Zhang, K., Ma, K., Xie, H., Zhang, Z., Cai, L., et al. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.77774 · Cited by 101
“Small-molecule inhibitor targeting FTO exhibits therapeutic efficacy in a PDX ccRCC mouse model Several FTO small-molecule inhibitors such as FB23-2 [6], Dac51 [27], R-2HG [28], and CS1/CS2 [29] have been reported to inhibit the demethylation activities of FTO.”
Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression
Qiao, Y., Su, M., Zhao, H., Liu, H., Wang, C., Dai, X., Liu, L., Liu, G., Sun, H., Sun, M., et al. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03032-9 · Cited by 101
“FTO had been widely studied in various cancers and reported to play crucial roles in the regulation of tumorigenesis [16, 28–32].”
BackgroundAMD1 upregulates hepatocellular carcinoma cells stemness by FTO mediated mRNA demethylation
Bian, X., Shi, D.-M., Xing, K., Zhou, H., Lu, L., Yu, D., & Wu, W. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.352 · Cited by 100
METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis
Pan, J., Liu, F., Xiao, X., Xu, R., Dai, L. X., Zhu, M., Xu, H., Xu, Y., Zhao, A., Zhou, W., et al. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02227-8 · Cited by 100
“FTO plays a central role in oral squamous cell carcinoma [22], hepatocellular carcinoma [23], bladder cancer [24], and acute myeloid leukemia [9, 25].”
BackgroundThe m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells
Kowalski‐Chauvel, A., Lacore, M. G., Arnauduc, F., Delmas, C., Toulas, C., Moyal, E. C., & Seva, C. (2020) · Cancers · doi:10.3390/cancers13010040 · Cited by 98
“also confirmed that decreasing FTO activity in GBM cell lines led to the inhibition of cell proliferation and viability likely through the regulation of Myc expression [13].”
BackgroundYang, Z., Cai, Z., Yang, C., Luo, Z., & Bao, X. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2022.104019 · Cited by 96
Wu, Y., Shao, W., Yan, M., Wang, Y., Xu, P., Huang, G., Li, X., Gregory, B. D., Yang, J. M., Wang, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48437-4 · Cited by 94
Self-citationDetailed resume of RNA m6A demethylases
Shen, D., Wang, B., Gao, Y., Zhao, L., Bi, Y., Zhang, J., Wang, N., Kang, H., Pang, J., Liu, Y., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.003 · Cited by 94
Signaling pathways in brain tumors and therapeutic interventions
Li, S., Wang, C., Chen, J., Lan, Y., Zhang, W., Kang, Z., Zheng, Y., Zhang, R., Yu, J., & Li, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01260-z · Cited by 105
“Interestingly, the anti-tumor potencies of R-2HG in impeding proliferation/survival of fat mass and obesity-associated (FTO)-high cancer cells via modulating the FTO/m6A/MYC/CEBPA signaling.(69) Moreover, the DNA repair activity of mammalian alkylation protein B homolog 2 (ALKBH2) and alkylation protein B homolog 3 (A…”
BackgroundSelf-citationRNA Modifications in Cancer: Functions, Mechanisms, and Therapeutic Implications
Huang, H., Weng, H., Deng, X., & Chen, J. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033357 · Cited by 92
Self-citationN6-methyladenosine (m6A) RNA modification in cancer stem cells
Ma, Z., & Ji, J. (2020) · Stem Cells · doi:10.1002/stem.3279 · Cited by 91
Yu, J.-T., Hu, X., Chen, H., Yang, Q., Li, H.-D., Dong, Y., Zhang, Y., Wang, J., Jin, J., Wu, Y., et al. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105286 · Cited by 91
Self-citationLiu, Z., Gao, L., Cheng, L., Lv, G., Sun, B., Wang, G., & Tang, Q. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-00944-y · Cited by 93
Gao, Z., Zha, X., Li, M., Xia, X., & Wang, S. (2024) · Cell & Bioscience · doi:10.1186/s13578-024-01286-6 · Cited by 91
“…Prostate adenocarcinoma [116] H3K9me3 ALKBH5 KDM4A binding to the ALKBH5 promoter promotes the transcription of ALKBH5 Intervertebral disc degeneration [117] between EZH2 and β-catenin, which interacts with the LEF/TCF binding elements in the FTO promoter region, thereby inhibiting FTO expression.”
Background
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
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
