RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
Open accessAbstract
The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.
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Less than 1% of the transcriptome depends on eIF4A, including key growth and cell death factors such as MYC, BCL2, MCL1, CDK4, CCND3, EZH2, NOTCH1.
“Specifically, they reveal that less than 1% of the transcriptome depends on eIF4A and, importantly, these eIF4A-dependent genes include key growth and cell death factors such as MYC, BCL2, MCL1, CDK4, CCND3, EZH2, NOTCH1, and others [21,23].”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [21]
The Discussion (page unavailable) identifies eIF4A-sensitive oncogene transcripts including MYC, NOTCH and BCL2, supporting the general point. But the Results, under “Ribosome footprinting” (page unavailable), report 281 transcripts with reduced translational efficiency among approximately 11,128 protein-coding genes—not less than 1%. The copy does not establish MCL1 or CDK4 as eIF4A-dependent; its mentions of CCND3 and EZH2 do not establish that designation either. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSilvestrol blocks translation of MYC and BCL2 mRNAs without affecting the GAPDH housekeeping gene across several lymphoma lines.
“Consistent with our previous findings [21], we see that silvestrol blocks the translation of the MYC and BCL2 mRNAs, without affecting the GAPDH housekeeping gene, across several lymphoma lines (SuDHL-4, SuDHL-6, SuDHL-10, Ly8) (Figure 1D).”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [21]
The Results section, “What transcripts are affected by Silvestrol?” (page unavailable), reports effects on MYC and says housekeeping genes showed no change in ribosome-footprint profiles; the Discussion also identifies BCL2 as a silvestrol-sensitive oncogene. Our copy does not establish unchanged GAPDH translation specifically. The named lymphoma lines are presented as the citing authors’ new observation, not a finding attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNRF2 activation increases baseline translation of eIF4A-dependent mRNAs with multiple GQ elements in their 5′ UTRs, such as MYC and BCL2.
“Consistently, by comparing mRNA and protein levels, we observe increased baseline translation of eIF4A-dependent mRNAs with multiple GQ elements in their 5′ UTRS, such as MYC (six GQ elements) and BCL2 (five GQ elements) [21] (Figure 3D,E and Figure S3C–E).”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [21]
The Discussion identifies MYC and BCL2 as eIF4A-sensitive transcripts and says such transcripts typically harbor several G-quadruplexes in their 5′ UTRs. Our copy does not substantiate the specific counts of six for MYC and five for BCL2. The increased baseline translation is presented in the citing sentence as the citing authors’ own observation, not a finding attributed to this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredEIF4A inhibitors block the pro-oncogenic translation program and produce powerful anti-cancer effects with limited effects in non-proliferative tissues.
“EIF4A inhibitors block this pro-oncogenic translation program and produce powerful anti-cancer effects with limited effects in non-proliferative tissues [21,23].”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [21]
The Results section ('eIF4A is an oncogene in T-ALL'; page not provided) reports that eIF4A inhibitors suppress oncoprotein expression, delay tumour growth, and are well tolerated in mice. The Extended Data describe toxicity assessments, but the paper does not specifically establish limited effects in non-proliferative tissues. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCR-1-31 B treatment was generally well tolerated and did not result in weight loss or mortality in mice.
“Consistent with our prior analysis of the in vivo toxicity [21], we find that the treatment was generally well tolerated and did not result in weight loss or mortality (Figure S1E).”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [21]
The Results section states that detailed toxicology found (±)-CR-31-B treatment well tolerated in mice. Extended Data Figure 3 describes weight monitoring, and the Toxicity studies procedures describe clinical observation, but our copy does not explicitly report no weight loss or treatment-related mortality. (LLM, conf=0.85)
Experimental — accuracy not yet measured
The sensitivity of MYC+/BCL2+ lymphomas to CR-1-31 B likely reflects eIF4A-dependent translation of both MYC and BCL2.
“It is especially active against aggressive MYC+/BCL2+ B cell lymphomas and this likely reflects the eIF4A-dependent translation of both MYC and BCL2.”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [21]
The Discussion (‘A selective mechanism of translational control’; page not provided) identifies MYC and BCL2 as eIF4A-sensitive oncogenes. The Results (‘eIF4A is an oncogene in T-ALL’; page not provided) report activity of CR-31-B against T-ALL, not aggressive MYC+/BCL2+ B-cell lymphomas. Thus the proposed mechanism is plausible from this paper, but the claimed sensitivity of that lymphoma subtype is not established by it. (LLM, conf=0.88)
Experimental — accuracy not yet measuredeIF4A helicase is uniquely required for translation of mRNAs with long and highly structured 5′ UTRs, including G-quadruplex structures.
“The eIF4A helicase is uniquely required for the translation of mRNAs with long and highly structured 5′ UTRs, including those with guanine tetrad sequences that are thought to fold into G-quadruplex (GQ) structures [21].”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [21]
The Discussion (page not supplied) links eIF4A-dependent translation to a subset of transcripts with long 5′ UTRs and G-quadruplex motifs. The Results (page not supplied) find eIF4A limiting for translation of a G-quadruplex reporter, but also note that other helicases may resolve G-quadruplexes. The paper does not establish that eIF4A is uniquely required for all mRNAs with long, highly structured 5′ UTRs. (LLM, conf=0.86)
Experimental — accuracy not yet measuredeIF4A-dependent mRNAs include key oncogenes such as MYC, BCL2, CDK6, KRAS, and YAP1, which are critical for tumorigenesis.
“Importantly, these mRNAs include key oncogenes such as MYC, BCL2, CDK6, KRAS, and YAP1 (15–17), which are critical for tumorigenesis.”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [15]
The Discussion (page not provided) identifies MYC, CDK6, and BCL2 among eIF4A-sensitive oncogene transcripts and says eIF4A is required for the expression of key oncogenes. Our copy does not identify KRAS or YAP1 as eIF4A-dependent mRNAs; its mention of oncogenic RAS in the Abstract concerns stimulation of cap-dependent translation, not dependence of KRAS mRNA on eIF4A. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA synthetic eIF4A inhibitor, CR-1-31B, has shown potent activity against many cancer cell lines and promising efficacy in several mouse models.
“A synthetic eIF4A inhibitor, CR-1-31B, has shown potent activity against many cancer cell lines and promising efficacy in several mouse models (15, 17, 20, 21, 32, 33).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [15]
The Results (‘eIF4A is an oncogene in T-ALL’; page not provided) identify synthetic (±)-CR-31-B as an eIF4A inhibitor and report that it delayed growth of KOPT-K1 tumours in mice. Extended Data Figure 2 reports testing CR in a panel of human T-ALL samples and cell lines, but the paper does not establish activity across many cancer cell-line types or efficacy for CR in several mouse models; some of the other mouse-model results concern silvestrol. (LLM, conf=0.85)
Experimental — accuracy not yet measuredeIF4A inhibitors target both isoforms, suppress translation of key oncogenes, and have demonstrated antitumor activity in a variety of cancers.
“eIF4A inhibitors, which target both isoforms, suppress translation of key oncogenes and have demonstrated antitumor activity in a variety of cancers (15, 17, 19–22).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [15]
The Results ('eIF4A is an oncogene in T-ALL'; page unavailable) state that Silvestrol and (±)-CR-31-B inhibit eIF4A1/2 and show antitumor effects in T-ALL. The Results ('What transcripts are affected by Silvestrol') and Discussion ('A selective mechanism of translational control') support suppression of key oncogene translation. But this paper demonstrates antitumor activity in T-ALL; the Discussion suggests activity in other cancers as a possibility, rather than demonstrating it across a variety of cancers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe RNA helicase component of eIF4F is required to unwind secondary structure in the 5′-UTR and initiate translation of mRNAs whose 5′-UTRs contain complex structures such as RNA G-quadruplexes.
“The RNA helicase component of this complex is required to unwind secondary structure in the 5′-UTR and initiate translation of mRNAs, specifically those RNAs whose 5′-UTRs contain complex structures such as RNA G-quadruplexes (15–17).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [15]
The Discussion (‘A selective mechanism of translational control’) identifies eIF4A as an RNA helicase and says that translation of a subset of mRNAs with 5′-UTR G-quadruplexes requires it. The Results (‘The (CGG)4 motif corresponds to G-quadruplexes’) support that dependence with a reporter assay, but the cited passages do not establish that eIF4A directly unwinds those structures to initiate translation. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIMP2 directly binds to the eIF4A protein, a member of the eIF4F translation initiation complex that acts as the helicase responsible for unwinding RNA secondary and tertiary structures to allow the ribosome to more efficiently translate mRNA into protein.
“IMP2 directly binds to the eIF4A protein, a member of the eIF4F translation initiation complex that acts as the helicase responsible for unwinding RNA secondary and tertiary structures to allow the ribosome to more efficiently translate mRNA into protein [33,34].”
From IMPlications of IMP2 in RNA Biology and Disease (2025) · cites this paper as [33]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredTranslation of MYC and BCL2 depends on eIF4A.
“Manual polysome fractionation experiments identified some eIF4A-dependent mRNAs such as MYC, BCL2, and MCL1 [22,23].”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [21]
Studies in mouse models of other cancers support the tolerability and efficacy of eIF4A inhibitors.
“Our results build on studies in mouse models of other cancers, including lymphoma, leukemia, breast, prostate, and pancreatic cancer, supporting the tolerability and efficacy of eIF4A inhibitors (15, 17, 20, 21, 38).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [15]
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Jean, G., Kahles, A., Sreedharan, V. T., Bona, F. D., & Rätsch, G. (2010) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1106s32 · Cited by 59 · see citing works
Self-citationAccurate detection of differential RNA processing
Drewe, P., Stegle, O., Hartmann, L., Kahles, A., Bohnert, R., Wachter, A., Borgwardt, K. M., & Rätsch, G. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt211 · Cited by 42 · see citing works
Self-citation
Flagged first, then by citations
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Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them
Leppek, K., Das, R., & Barna, M. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.103 · Cited by 949 · see citing works
Targeting the translation machinery in cancer
Bhat, M., Robichaud, N., Hulea, L., Sonenberg, N., Pelletier, J., & Topisirovic, I. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4505 · Cited by 799 · see citing works
Self-citationRegulation of cancer cell metabolism: Oncogenic MYC in the driver’s seat
Dong, Y., Tu, R., Liu, H., & Qing, G. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00235-2 · Cited by 405 · see citing works
New frontiers in translational control of the cancer genome
Truitt, M. L., & Ruggero, D. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.27 · Cited by 378 · see citing works
Targeting the eIF4F Translation Initiation Complex: A Critical Nexus for Cancer Development
Pelletier, J., Graff, J., Ruggero, D., & Sonenberg, N. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2789 · Cited by 367 · see citing works
Self-citationExtensive identification and analysis of conserved small ORFs in animals
Mackowiak, S. D., Zauber, H., Bielow, C., Thiel, D., Kutz, K., Calviello, L., Mastrobuoni, G., Rajewsky, N., Kempa, S., Selbach, M., et al. (2015) · Genome Biology · doi:10.1186/s13059-015-0742-x · Cited by 227 · see citing works
Rubio, C. A., Weisburd, B., Holderfield, M., Arias, C., Fang, E., DeRisi, J. L., & Fanidi, A. (2014) · Genome Biology · doi:10.1186/s13059-014-0476-1 · Cited by 200 · see citing works
G-quadruplex unwinding helicases and their function <i>in vivo</i>
Sauer, M., & Paeschke, K. (2017) · Biochemical Society Transactions · doi:10.1042/bst20170097 · Cited by 179 · see citing works
Ernst, J. T., Thompson, P. A., Nilewski, C., Sprengeler, P. A., Sperry, S., Packard, G., Michels, T., Xiang, A., Tran, C., Wegerski, C. J., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00182 · Cited by 150 · see citing works
eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma
Chan, K., Robert, F., Oertlin, C., Kapeller-Libermann, D., Avizonis, D., Gutierrez, J., Handly-Santana, A., Doubrovin, M., Park, J., Schoepfer, C., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13086-5 · Cited by 106 · see citing works
Self-citationMolecular Pathways: The eIF4F Translation Initiation Complex—New Opportunities for Cancer Treatment
Malka-Mahieu, H., Newman, M., Désaubry, L., Robert, C., & Vagner, S. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2362 · Cited by 105 · see citing works
Krishnamoorthy, G. P., Davidson, N. R., Leach, S. D., Zhao, Z., Lowe, S. W., Lee, G., Landa, I., Nagarajah, J., Saqcena, M., Singh, K., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0606 · Cited by 94 · see citing works
Self-citationAmidino-Rocaglates: A Potent Class of eIF4A Inhibitors
Chu, J., Zhang, W., Cencic, R., Devine, W. G., Beglov, D., Henkel, T., Brown, L. E., Vajda, S., Porco, J. A., & Pelletier, J. (2019) · Cell Chemical Biology · doi:10.1016/j.chembiol.2019.08.008 · Cited by 74 · see citing works
Self-citationThe Role of Translation Control in Tumorigenesis and Its Therapeutic Implications
Xu, Y., & Ruggero, D. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033420 · Cited by 67 · see citing works
Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma
Wang, Q., Zhu, J., Wang, Y.-W., Dai, Y., Wang, Y.-L., Wang, C., Liu, J., Baker, A., Colburn, N. H., & Yang, H.-S. (2017) · Oncogene · doi:10.1038/onc.2017.228 · Cited by 67 · see citing works
Translational dysregulation in cancer: eIF4A isoforms and sequence determinants of eIF4A dependence
Raza, F., Waldron, J. A., & Quesne, J. L. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150163 · Cited by 61 · see citing works
Thompson, P. A., Eam, B., Young, N. P., Fish, S., Chen, J., Barrera, M., Howard, H., Sung, E., Parra, A., Staunton, J., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0973 · Cited by 50 · see citing works
Targeting Translation of mRNA as a Therapeutic Strategy in Cancer
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Ligands stimulating antitumour immunity as the next G-quadruplex challenge
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“Emetine • Transcriptome-wide downregulation [34]”
BackgroundTargeting eIF4A-Dependent Translation of KRAS Signaling Molecules
Singh, K., Lin, J., Lecomte, N., Mohan, P., Gokce, A., Sanghvi, V. R., Jiang, M., Grbovic-Huezo, O., Burčul, A., Stark, S. G., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2929 · Cited by 39 · see citing works
Self-citationNRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
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“Specifically, they reveal that less than 1% of the transcriptome depends on eIF4A and, importantly, these eIF4A‐dependent genes include key growth and cell death factors such as MYC, BCL2, MCL1, CDK4, CCND3, EZH2, NOTCH1, and others [21,23].”
BackgroundResultInfluentialSelf-citationSmall-molecule RNA therapeutics to target prostate cancer
Kuzuoglu-Ozturk, D., Nguyen, H. G., Xue, L., Figueredo, E., Subramanyam, V., Liu, I., Bonitto, K., Noronha, A., Dabrowska, A., Cowan, J. E., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.02.027 · Cited by 24 · see citing works
Chang, L.-S., Oblinger, J. L., Burns, S. S., Huang, J., Anderson, L. W., Hollingshead, M. G., Shen, R., Pan, L., Agarwal, G., Ren, Y., et al. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0809 · Cited by 22 · see citing works
IMPlications of IMP2 in RNA Biology and Disease
Das, J., Busia-Bourdain, O., Khan, K. M., & Wolfe, A. L. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062415 · Cited by 3 · see citing works
“IMP2 directly binds to the eIF4A protein, a member of the eIF4F translation initiation complex that acts as the helicase responsible for unwinding RNA secondary and tertiary structures to allow the ribosome to more efficiently translate mRNA into protein [33,34].”
Self-citationTargeting eIF4A-dependent translation in genetically complex sarcoma
Kim, Y.-M., Mohan, P., Sehrawat, U., Seffar, E., De Queiroz, R. M., Chadalavada, K., Persaud, N., Okada, T., Kulkarni, A., Lin, J., et al. (2026) · JCI Insight · doi:10.1172/jci.insight.192936
Self-citation
- Authors
- Wolfe, A. L., Singh, K., Zhong, Y., Drewe, P., Rajasekhar, V. K., Sanghvi, V. R., Mavrakis, K. J., Jiang, M., Roderick, J. E., Van der Meulen, J., Schatz, J. H., Rodrigo, C. M., Zhao, C., Rondou, P., de Stanchina, E., Teruya-Feldstein, J., Kelliher, M. A., Speleman, F., Porco, J. A., Pelletier, J., Rätsch, G., & Wendel, H.-G.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Massachusetts Chan Medical School (US)
- Boston University (US)
- Ghent University Hospital (BE)
- Institut du cancer Rosalind & Morris Goodman (CA)
- Corresponding author
- Rätsch, Gunnar
- Wendel, Hans-Guido
- ORCID
- Venue
- Nature
- Published
- 2014-07-27
- Volume
- 513
- Issue
- 7516
- Pages
- 65-70
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4492470
- OpenAlex
- W1965163574
- Cited by
- 635
- References
- 56
- Citations by year
- 2026: 35 · 2025: 48 · 2024: 47 · 2023: 50 · 2022: 68 · 2021: 57 · 2020: 63 · 2019: 61 · 2018: 52 · 2017: 47 · 2016: 56 · 2015: 44 · 2014: 7
- FWCI
- 21.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- OpenBU (Boston University) (submittedVersion)
- Funders
- Leukemia and Lymphoma Society
- European Commission (316861)
- Fonds Wetenschappelijk Onderzoek (G.0198.08)
- Universiteit Gent
- Vlaamse regering
- Fondation contre le Cancer
- National Institutes of Health
- Canadian Institutes of Health Research (MOP-10653)
- National Cancer Institute (R01-CA142798-01, R01CA142798, P30CA008748)
- National Institute of General Medical Sciences (GM067041, P50GM067041, GM-073855, R01GM073855)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- RNA G-quadruplex, eIF4A, RNA helicase, translational regulation, silvestrol, 5' untranslated region, T-cell acute lymphoblastic leukemia, ribosome profiling, epigenetic regulators, eIF4F, BRAF inhibitors, melanoma, anticancer drug targets
- MeSH terms
- Animals, Antineoplastic Agents, Phytogenic, Base Sequence, Benzofurans, Female, Humans, Mice, Inbred C57BL, Ribosomes, Transcription Factors, Transcription, Genetic, Protein Biosynthesis, Triterpenes, Oncogene Proteins, 5' Untranslated Regions, Eukaryotic Initiation Factor-4A, Epigenesis, Genetic, Cell Line, Tumor, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, G-Quadruplexes, Nucleotide Motifs
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