Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement
Open accessAbstract
Upon exposure to stress, tRNAs are enzymatically cleaved, yielding distinct classes of tRNA-derived fragments (tRFs), yielding distinct classes of tRFs. We identify a novel class of tRFs derived from tRNA(Glu), tRNA(Asp), tRNA(Gly), and tRNA(Tyr) that, upon induction, suppress the stability of multiple oncogenic transcripts in breast cancer cells by displacing their 3' untranslated regions (UTRs) from the RNA-binding protein YBX1. This mode of post-transcriptional silencing is sequence specific, as these fragments all share a common motif that matches the YBX1 recognition sequence. Loss-of-function and gain-of-function studies, using anti-sense locked-nucleic acids (LNAs) and synthetic RNA mimetics, respectively, revealed that these fragments suppress growth under serum-starvation, cancer cell invasion, and metastasis by breast cancer cells. Highly metastatic cells evade this tumor-suppressive pathway by attenuating the induction of these tRFs. Our findings reveal a tumor-suppressive role for specific tRNA-derived fragments and describe a molecular mechanism for their action. This transcript displacement-based mechanism may generalize to other tRNA, ribosomal-RNA, and sno-RNA fragments.
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
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?
YBX1 is a multifunctional RBP that stabilizes mRNAs and regulates RNA splicing.
“YBX1 is a multifunctional RBP that stabilizes mRNAs and regulates RNA splicing33,34.”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [34]
The Results section describes YBX1 as a multifunctional RNA-binding protein, and the Introduction and Discussion say it stabilizes target transcripts. Our copy does not say that YBX1 regulates RNA splicing; a search for splicing found no supporting passage. Page numbers were not available in the indexed copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPreviously reported YBX1-stabilized transcripts were preferentially repressed in miR-140G/G and miR-140G/+ chondrocytes as compared with miR-140−/− chondrocytes.
“In addition, previously reported YBX1-stabilized transcripts were preferentially repressed in miR-140G/G and miR-140G/+ chondrocytes as compared with miR-140−/− chondrocytes”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [34]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The widespread regulation of microRNA biogenesis, function and decay
Krol, J., Loedige, I., & Filipowicz, W. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2843 · Cited by 4,672 · see citing works
Györffy, B., Lanczky, A., Eklund, A. C., Denkert, C., Budczies, J., Li, Q., & Szallasi, Z. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0674-9 · Cited by 4,169 · see citing works
Targeting hypoxia in cancer therapy
Wilson, W. R., & Hay, M. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3064 · Cited by 3,172 · see citing works
Regulation of Mammalian O <sub>2</sub> Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.551 · Cited by 1,914 · see citing works
HITS-CLIP yields genome-wide insights into brain alternative RNA processing
Licatalosi, D. D., Mele, A., Fak, J. J., Ule, J., Kayikci, M., Chi, S. W., Clark, T. A., Schweitzer, A. C., Blume, J. E., Wang, X., et al. (2008) · Nature · doi:10.1038/nature07488 · Cited by 1,352 · see citing works
Hypoxia, DNA repair and genetic instability
Bristow, R. G., & Hill, R. P. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2344 · Cited by 1,140 · see citing works
Flagged first, then by citations
Research works printed but not linked: 25
- Borek E Baliga BS Gehrke CW Kuo CW Belman S Troll W Waalkes TP 1977 High turnover rate of transfer RNA in tumor tissue Cancer research 37 3362 3366 884680
- Cole C Sobala A Lu C Thatcher SR Bowman A Brown JWS Green PJ Barton GJ Hutvagner G 2009 Filtering of deep sequencing data reveals the existence of abundant Dicer-dependent small RNAs derived from tRNAs Rna 15 2147 2160 19850906 PMC2779667
- Elemento O Slonim N Tavazoie S 2007 A universal framework for regulatory element discovery across all Genomes and data types Molecular cell 28 337 350 17964271 PMC2900317
- Emara MM Ivanov P Hickman T Dawra N Tisdale S Kedersha N Hu GF Anderson P 2010 Angiogenin-induced tRNA-derived Stress-induced RNAs Promote Stress-induced Stress Granule Assembly Journal of Biological Chemistry 285 10959 10968 20129916 PMC2856301
- Fu H Feng J Liu Q Sun F Tie Y Zhu J Xing R Sun Z Zheng X 2009 Stress induces tRNA cleavage by angiogenin in mammalian cells FEBS Lett 583 437 442 19114040
- Gebetsberger J Polacek N 2013 Slicing tRNAs to boost functional ncRNA diversity RNA biology 10 PMC3917982 24351723
- Gyorffy B Lanczky A Szallasi Z 2012 Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients Endocr-Relat Cancer 19 197 208 22277193
- Ivanov P Emara MM Villen J Gygi SP Anderson P 2011 Angiogenin-Induced tRNA Fragments Inhibit Translation Initiation Molecular cell 43 613 623 21855800 PMC3160621
- Jurchott K Kuban RJ Krech T Bluthgen N Stein U Walther W Friese C Kielbasa SM Ungethum U Lund P 2010 Identification of Y-Box Binding Protein 1 As a Core Regulator of MEK/ERK Pathway-Dependent Gene Signatures in Colorectal Cancer Cells Plos Genet 6 PMC2996331 21170361
- Karaca E Weitzer S Pehlivan D Shiraishi H Gogakos T Hanada T Jhangiani SN Wiszniewski W Withers M Campbell IM 2014 Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function Cell 157 636 650 24766809 PMC4146440
- Lasham A Samuel W Cao H Patel R Mehta R Stern JL Reid G Woolley AG Miller LD Black MA 2012 YB-1, the E2F pathway, and regulation of tumor cell growth Journal of the National Cancer Institute 104 133 146 22205655 PMC4817305
- Lee YS Shibata Y Malhotra A Dutta A 2009 A novel class of small RNAs: tRNA-derived RNA fragments (tRFs) Genes & Development 23 2639 2649 19933153 PMC2779758
- Lujambio A Lowe SW 2012 The microcosmos of cancer Nature 482 347 355 22337054 PMC3509753
- Matsumoto K Bay BH 2005 Significance of the Y-box proteins in human cancers Journal of molecular and genetic medicine: an international journal of biomedical research 1 11 17 19565008 PMC2702063
- Minn AJ Gupta GP Siegel PM Bos PD Shu W Giri DD Viale A Olshen AB Gerald WL Massague J 2005 Genes that mediate breast cancer metastasis to lung Nature 436 518 524 16049480 PMC1283098
- Moyer MW 2012 Targeting hypoxia brings breath of fresh air to cancer therapy Nature medicine 18 636 637 22561804
- Salmena L Poliseno L Tay Y Kats L Pandolfi PP 2011 A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146 353 358 21802130 PMC3235919
- Semenza GL 1999 Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1 Annual review of cell and developmental biology 15 551 578 10611972
- Shen C Kaelin WG Jr 2013 The VHL/HIF axis in clear cell renal carcinoma Seminars in cancer biology 23 18 25 22705278 PMC3663044
- Speer J Gehrke CW Kuo KC Waalkes TP Borek E 1979 tRNA breakdown products as markers for cancer Cancer 44 2120 2123 509391
- Thompson DM Parker R 2009 Stressing out over tRNA cleavage Cell 138 215 219 19632169
- Uchiumi T Fotovati A Sasaguri T Shibahara K Shimada T Fukuda T Nakamura T Izumi H Tsuzuki T Kuwano M 2006 YB-1 is important for an early stage embryonic development - Neural tube formation and cell proliferation Journal of Biological Chemistry 281 40440 40449 17082189
- Ule J Jensen K Mele A Darnell RB 2005 CLIP: a method for identifying protein-RNA interaction sites in living cells Methods 37 376 386 16314267
- Wu Y Yamada S Izumi H Li Z Shimajiri S Wang KY Liu YP Kohno K Sasaguri Y 2012 Strong YB-1 expression is associated with liver metastasis progression and predicts shorter disease-free survival in advanced gastric cancer J Surg Oncol 105 724 730 22215526
- Zhang CL Darnell RB 2011 Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP data Nature Biotechnology 29 607 U686 PMC3400429 21633356
Cited by
Sorted by citations
RNA delivery by extracellular vesicles in mammalian cells and its applications
O’Brien, K., Breyne, K., Ughetto, S., Laurent, L. C., & Breakefield, X. O. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0251-y · Cited by 1,811 · see citing works
The role of non-coding RNAs in oncology
Slack, F. J., & Chinnaiyan, A. M. (2019) · Cell · doi:10.1016/j.cell.2019.10.017 · Cited by 1,619 · see citing works
Regulation of exosome production and cargo sorting
Wei, H., Chen, Q., Lin, L., Sha, C., Li, T., Liu, Y., Yin, X., Xu, Y., Chen, L., Gao, W., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.53671 · Cited by 385 · see citing works
Metabolic Inputs into the Epigenome
Sharma, U., & Rando, O. J. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.02.003 · Cited by 167 · see citing works
Yang, J.-Y., Deng, X.-Y., Li, Y.-S., Ma, X.-C., Feng, J.-X., Yu, B., Chen, Y., Luo, Y.-L., Wang, X., Chen, M.-L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03544-x · Cited by 124 · see citing works
A mouse tissue atlas of small noncoding RNA
Isakova, A., Fehlmann, T., Keller, A., & Quake, S. R. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2002277117 · Cited by 119 · see citing works
Gain-of-function mutation of microRNA-140 in human skeletal dysplasia
Grigelioniene, G., Suzuki, H. I., Taylan, F., Mirzamohammadi, F., Borochowitz, Z. U., Ayturk, U. M., Tzur, S., Horemuzova, E., Lindstrand, A., Weis, M. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0353-2 · Cited by 103 · see citing works
“10e) 34 .”
YBX1 as an oncogenic factor in T-cell acute lymphoblastic leukemia
Li, H., Zhang, D., Fu, Q., Wang, S., Wang, Z., Zhang, X., Chen, X., Zhu, X., An, N., Chen, Y., et al. (2023) · Blood Advances · doi:10.1182/bloodadvances.2022009648 · Cited by 21 · see citing works
- Authors
- Goodarzi, H., Liu, X., Nguyen, H. C. B., Zhang, S., Fish, L., & Tavazoie, S. F.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- Tavazoie, Sohail F.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 161
- Issue
- 4
- Pages
- 790-802
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4457382
- OpenAlex
- W1832399013
- Cited by
- 949
- References
- 6
- Citations by year
- 2026: 71 · 2025: 102 · 2024: 119 · 2023: 87 · 2022: 149 · 2021: 104 · 2020: 93 · 2019: 71 · 2018: 53 · 2017: 38 · 2016: 44 · 2015: 17
- FWCI
- 20.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Defense
- National Institutes of Health (T32CA009673-36A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- tRNA-derived fragments, YB-1, breast cancer, post-transcriptional gene silencing, 3' untranslated region, RNA-binding proteins, metastasis, tumor suppression, locked nucleic acid
- MeSH terms
- Breast Neoplasms, Humans, Neoplasm Metastasis, Oligonucleotides, RNA, Transfer, Sequence Analysis, RNA, Y-Box-Binding Protein 1, HEK293 Cells, RNA, Small Untranslated
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
