Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The plasticity of mRNA translation during cancer progression and therapy resistance

Nature Reviews Cancer volume 21, pages 558–577 (2021)Cite this article

Subjects

Abstract

Translational control of mRNAs during gene expression allows cells to promptly and dynamically adapt to a variety of stimuli, including in neoplasia in response to aberrant oncogenic signalling (for example, PI3K–AKT–mTOR, RAS–MAPK and MYC) and microenvironmental stress such as low oxygen and nutrient supply. Such translational rewiring allows rapid, specific changes in the cell proteome that shape specific cancer phenotypes to promote cancer onset, progression and resistance to anticancer therapies. In this Review, we illustrate the plasticity of mRNA translation. We first highlight the diverse mechanisms by which it is regulated, including by translation factors (for example, eukaryotic initiation factor 4F (eIF4F) and eIF2), RNA-binding proteins, tRNAs and ribosomal RNAs that are modulated in response to aberrant intracellular pathways or microenvironmental stress. We then describe how translational control can influence tumour behaviour by impacting on the phenotypic plasticity of cancer cells as well as on components of the tumour microenvironment. Finally, we highlight the role of mRNA translation in the cellular response to anticancer therapies and its promise as a key therapeutic target.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The process of mRNA translation.
Fig. 2: Plasticity of translational control.
Fig. 3: Oncogenic signalling activates eIF4F.
Fig. 4: Stress-induced shutdown of translation.
Fig. 5: Translational control of cancer cell plasticity.
Fig. 6: Translational control of cancer cell immune evasion.
Fig. 7: Translational control of resistance to anticancer drugs.

Similar content being viewed by others

References

  1. Schwanhausser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).

    Article  PubMed  CAS  Google Scholar 

  2. Tian, Q. et al. Integrated genomic and proteomic analyses of gene expression in mammalian cells. Mol. Cell Proteom. 3, 960–969 (2004).

    Article  CAS  Google Scholar 

  3. Vogel, C. et al. Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line. Mol. Syst. Biol. 6, 400 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Zhang, B. et al. Proteogenomic characterization of human colon and rectal cancer. Nature 513, 382–387 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu, Y., Beyer, A. & Aebersold, R. On the dependency of cellular protein levels on mRNA abundance. Cell 165, 535–550 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Rajasekhar, V. K. et al. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol. Cell 12, 889–901 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Silvera, D., Formenti, S. C. & Schneider, R. J. Translational control in cancer. Nat. Rev. Cancer 10, 254–266 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Truitt, M. L. & Ruggero, D. New frontiers in translational control of the cancer genome. Nat. Rev. Cancer 16, 288–304 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. El-Naggar, A. M. & Sorensen, P. H. Translational control of aberrant stress responses as a hallmark of cancer. J. Pathol. 244, 650–666 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Xu, Y. & Ruggero, D. The role of translation control in tumorigenesis and its therapeutic implications. Annu. Rev. Cancer Biol. 4, 437–457 (2020).

    Article  Google Scholar 

  12. Malabou, C. & Shread, C. Plasticity at the Dusk of Writing Dialectic, Destruction, Deconstruction (Columbia University Press, 2010).

  13. Leprivier, G. et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153, 1064–1079 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Falletta, P. et al. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev. 31, 18–33 (2017). This article describes that, in response to microenvironmental cues in melanoma, eIF2α phosphorylation and the induction of ATF4 expression reprogrammes translation, leading to the suppression of MITF expression and the switch to a proinvasive phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rapino, F. et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558, 605–609 (2018). This study demonstrates that resistance to BRAF inhibitors is driven by the U34 enzyme-mediated codon bias translation of HIF1A mRNA downstream of PI3K activation, supporting a metabolic reprogramming towards glycolysis.

    Article  CAS  PubMed  Google Scholar 

  16. Jewer, M. et al. Translational control of breast cancer plasticity. Nat. Commun. 11, 2498 (2020). This study shows that hypoxia, mTOR inhibition and chemotherapeutics induce the translation of specific 5′ UTR isoforms of NANOG, SNAI1 and NODAL mRNAs, the protein products of which induce the acquisition of stem cell-like properties in breast cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jackson, R. J., Hellen, C. U. & Pestova, T. V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 11, 113–127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hinnebusch, A. G. Structural insights into the mechanism of scanning and start codon recognition in eukaryotic translation initiation. Trends Biochem. Sci. 42, 589–611 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Knight, J. R. P. et al. Control of translation elongation in health and disease. Dis. Model. Mech. 13, dmm043208 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hellen, C. U. T. Translation termination and ribosome recycling in eukaryotes. Cold Spring Harb. Perspect. Biol. 10, a032656 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dever, T. E. & Green, R. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb. Perspect. Biol. 4, a013706 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Pelletier, J. & Sonenberg, N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 334, 320–325 (1988).

    Article  CAS  PubMed  Google Scholar 

  23. Weingarten-Gabbay, S. et al. Comparative genetics. Systematic discovery of cap-independent translation sequences in human and viral genomes. Science 351, aad4939 (2016).

    Article  PubMed  CAS  Google Scholar 

  24. King, H. A., Cobbold, L. C. & Willis, A. E. The role of IRES trans-acting factors in regulating translation initiation. Biochem. Soc. Trans. 38, 1581–1586 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Komar, A. A. & Hatzoglou, M. Cellular IRES-mediated translation: the war of ITAFs in pathophysiological states. Cell Cycle 10, 229–240 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ingolia, N. T., Lareau, L. F. & Weissman, J. S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147, 789–802 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Somers, J., Poyry, T. & Willis, A. E. A perspective on mammalian upstream open reading frame function. Int. J. Biochem. Cell Biol. 45, 1690–1700 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hinnebusch, A. G., Ivanov, I. P. & Sonenberg, N. Translational control by 5′-untranslated regions of eukaryotic mRNAs. Science 352, 1413–1416 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. He, P. C. & He, C. m6A RNA methylation: from mechanisms to therapeutic potential. EMBO J. 40, e105977 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang, X. et al. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388–1399 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shi, H. et al. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res. 27, 315–328 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Meyer, K. D. et al. 5′ UTR m6A promotes cap-independent translation. Cell 163, 999–1010 (2015). This study, together with the studies by Coots et al. (2017) and Zhou et al. (2015), shows that m6A methylation in the 5′ UTR promotes cap-independent translation, especially during stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Coots, R. A. et al. m6A facilitates eIF4F-independent mRNA translation. Mol. Cell 68, 504–514 e507 (2017). This study, together with the studies by Meyer et al. (2015) and Zhou et al. (2015), shows that m6A methylation in the 5′ UTR promotes the initiation of cap-independent translation, especially during stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Choe, J. et al. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 561, 556–560 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lin, S., Choe, J., Du, P., Triboulet, R. & Gregory, R. I. The m6A methyltransferase METTL3 promotes translation in human cancer cells. Mol. Cell 62, 335–345 (2016). This article demonstrates that, in cancer cells, METTL3 promotes a selective cap-dependent translation of mRNAs that contain m6A methylation near the stop codon.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mao, Y. et al. m6A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2. Nat. Commun. 10, 5332 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Richter, J. D. & Coller, J. Pausing on polyribosomes: make way for elongation in translational control. Cell 163, 292–300 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hanson, G. & Coller, J. Codon optimality, bias and usage in translation and mRNA decay. Nat. Rev. Mol. Cell Biol. 19, 20–30 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Yao, R. W., Wang, Y. & Chen, L. L. Cellular functions of long noncoding RNAs. Nat. Cell Biol. 21, 542–551 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Duchaine, T. F. & Fabian, M. R. Mechanistic insights into microRNA-mediated gene silencing. Cold Spring Harb. Perspect. Biol. 11, a032771 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Vaupel, P. & Harrison, L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9, 4–9 (2004).

    Article  PubMed  Google Scholar 

  43. Haghighat, A., Mader, S., Pause, A. & Sonenberg, N. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J. 14, 5701–5709 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hsieh, A. C. et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17, 249–261 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. She, Q. B. et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 18, 39–51 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Waskiewicz, A. J. et al. Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo. Mol. Cell Biol. 19, 1871–1880 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jones, R. M. et al. An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc. Mol. Cell Biol. 16, 4754–4764 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lin, C. J., Cencic, R., Mills, J. R., Robert, F. & Pelletier, J. c-Myc and eIF4F are components of a feedforward loop that links transcription and translation. Cancer Res. 68, 5326–5334 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Larsson, O. et al. Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. Cancer Res. 67, 6814–6824 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Avdulov, S. et al. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5, 553–563 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Crew, J. P. et al. Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br. J. Cancer 82, 161–166 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Topisirovic, I., Ruiz-Gutierrez, M. & Borden, K. L. Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res. 64, 8639–8642 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Truitt, M. L. et al. Differential requirements for eIF4E dose in normal development and cancer. Cell 162, 59–71 (2015). This study uses an eIF4E haploinsufficient mouse model to demonstrate that a 50% reduction in eIF4E expression limits cellular transformation but not normal development. eIF4e dose is critical in driving the selective translation of mRNAs encoding regulators of oxidative stress responses, which harbour a CERT regulatory element in their 5′ UTR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nasr, Z., Robert, F., Porco, J. A. Jr., Muller, W. J. & Pelletier, J. eIF4F suppression in breast cancer affects maintenance and progression. Oncogene 32, 861–871 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Wendel, H. G. et al. Dissecting eIF4E action in tumorigenesis. Genes Dev. 21, 3232–3237 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Robichaud, N. et al. Translational control in the tumor microenvironment promotes lung metastasis: phosphorylation of eIF4E in neutrophils. Proc. Natl Acad. Sci. USA 115, E2202–E2209 (2018). By using an eIF4E phospho-mutant mouse model, this study demonstrates that phosphorylation of eIF4E in the TME is a critical determinant of metastatic progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Parkin, N., Darveau, A., Nicholson, R. & Sonenberg, N. cis-acting translational effects of the 5′ noncoding region of c-myc mRNA. Mol. Cell Biol. 8, 2875–2883 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Rosenwald, I. B., Lazaris-Karatzas, A., Sonenberg, N. & Schmidt, E. V. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol. Cell Biol. 13, 7358–7363 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Koromilas, A. E., Lazaris-Karatzas, A. & Sonenberg, N. mRNAs containing extensive secondary structure in their 5′ non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E. EMBO J. 11, 4153–4158 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rubio, C. A. et al. Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation. Genome Biol. 15, 476 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Wolfe, A. L. et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513, 65–70 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Levy, S., Avni, D., Hariharan, N., Perry, R. P. & Meyuhas, O. Oligopyrimidine tract at the 5′ end of mammalian ribosomal protein mRNAs is required for their translational control. Proc. Natl Acad. Sci. USA 88, 3319–3323 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Avni, D., Shama, S., Loreni, F. & Meyuhas, O. Vertebrate mRNAs with a 5′-terminal pyrimidine tract are candidates for translational repression in quiescent cells: characterization of the translational cis-regulatory element. Mol. Cell Biol. 14, 3822–3833 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012). This article, along with the article by Hsieh et al. (2012), identifies TOP sequence and TOP-like PRTE motifs as mRNA regulatory elements conferring mTOR-dependent translational selectivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012). This article, along with the article by Thoreen et al. (2012), identifies TOP sequence and TOP-like PRTE motifs as mRNA regulatory elements conferring mTOR-dependent translational selectivity. This study also links mTOR-dependent translational regulation with prostate cancer invasiveness.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jefferies, H. B., Reinhard, C., Kozma, S. C. & Thomas, G. Rapamycin selectively represses translation of the “polypyrimidine tract” mRNA family. Proc. Natl Acad. Sci. USA 91, 4441–4445 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tang, H. et al. Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol. Cell Biol. 21, 8671–8683 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cunningham, J. T., Moreno, M. V., Lodi, A., Ronen, S. M. & Ruggero, D. Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 157, 1088–1103 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang, X. et al. Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling. Mol. Cell Biol. 34, 4088–4103 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Faller, W. J. et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 517, 497–500 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Felton-Edkins, Z. A. et al. The mitogen-activated protein (MAP) kinase ERK induces tRNA synthesis by phosphorylating TFIIIB. EMBO J. 22, 2422–2432 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gomez-Roman, N., Grandori, C., Eisenman, R. N. & White, R. J. Direct activation of RNA polymerase III transcription by c-Myc. Nature 421, 290–294 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Wei, Y., Tsang, C. K. & Zheng, X. F. Mechanisms of regulation of RNA polymerase III-dependent transcription by TORC1. EMBO J. 28, 2220–2230 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Goodarzi, H. et al. Modulated expression of specific tRNAs drives gene expression and cancer progression. Cell 165, 1416–1427 (2016). This article, along with the article by Gingold et al. (2014), shows how the expression of a specific tRNA pool reflects codon usage of specific mRNAs involved in cancer phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gingold, H. et al. A dual program for translation regulation in cellular proliferation and differentiation. Cell 158, 1281–1292 (2014). This article, along with the article by Goodarzi et al. (2016), shows how the expression of a specific tRNA pool reflects codon usage of specific mRNAs involved in cancer phenotypes. This study also demonstrates that proliferating and differentiated cells show opposite expression of the tRNA pool that corresponds to codons enriched in proliferation-related or differentiation-related genes, respectively.

    Article  CAS  PubMed  Google Scholar 

  76. Pavon-Eternod, M. et al. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 37, 7268–7280 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, Z. et al. Global analysis of tRNA and translation factor expression reveals a dynamic landscape of translational regulation in human cancers. Commun. Biol. 1, 234 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Barbieri, I. & Kouzarides, T. Role of RNA modifications in cancer. Nat. Rev. Cancer 20, 303–322 (2020).

    Article  CAS  PubMed  Google Scholar 

  79. Ohshio, I. et al. ALKBH8 promotes bladder cancer growth and progression through regulating the expression of survivin. Biochem. Biophys. Res. Commun. 477, 413–418 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Delaunay, S. et al. Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer. J. Exp. Med. 213, 2503–2523 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chan, J. C. et al. AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer. Sci. Signal. 4, ra56 (2011).

    Article  PubMed  CAS  Google Scholar 

  82. Hannan, K. M. et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol. Cell Biol. 23, 8862–8877 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Barna, M. et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456, 971–975 (2008). This study uses genetic mouse models to demonstrate that the ability of MYC to increase protein synthesis is necessary to drive cancer initiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xue, S. et al. RNA regulons in Hox 5′ UTRs confer ribosome specificity to gene regulation. Nature 517, 33–38 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Kondrashov, N. et al. Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning. Cell 145, 383–397 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shi, Z. et al. Heterogeneous ribosomes preferentially translate distinct subpools of mRNAs genome-wide. Mol. Cell 67, 71–83.e77 (2017). This study reveals that ribosomal protein heterogeneity determines the ability of ribosomes to translate specific subpools of mRNAs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kampen, K. R. et al. The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL. Leukemia 33, 319–332 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. Girardi, T. et al. The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling. Leukemia 32, 809–819 (2018).

    Article  CAS  PubMed  Google Scholar 

  89. Marcel, V. et al. p53 acts as a safeguard of translational control by regulating fibrillarin and rRNA methylation in cancer. Cancer Cell 24, 318–330 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yoon, A. et al. Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita. Science 312, 902–906 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Bellodi, C., Kopmar, N. & Ruggero, D. Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenita. EMBO J. 29, 1865–1876 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lahr, R. M. et al. La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs. eLife 6, e24146 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Fonseca, B. D. et al. La-related protein 1 (LARP1) represses terminal oligopyrimidine (TOP) mRNA translation downstream of mTOR complex 1 (mTORC1). J. Biol. Chem. 290, 15996–16020 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Aoki, K. et al. LARP1 specifically recognizes the 3′ terminus of poly(A) mRNA. FEBS Lett. 587, 2173–2178 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Gentilella, A. et al. Autogenous control of 5′TOP mRNA stability by 40S ribosomes. Mol. Cell 67, 55–70 e54 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cassidy, K. C. et al. Capturing the mechanism underlying TOP mRNA binding to LARP1. Structure 27, 1771–1781 e1775 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Tcherkezian, J. et al. Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5′TOP mRNA translation. Genes Dev. 28, 357–371 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mura, M. et al. LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression. Oncogene 34, 5025–5036 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Holmes, B. et al. mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma. Oncogene 37, 732–743 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Topisirovic, I. et al. Stability of eukaryotic translation initiation factor 4E mRNA is regulated by HuR, and this activity is dysregulated in cancer. Mol. Cell Biol. 29, 1152–1162 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Pereira, B., Billaud, M. & Almeida, R. RNA-binding proteins in cancer: old players and new actors. Trends Cancer 3, 506–528 (2017).

    Article  CAS  PubMed  Google Scholar 

  102. Qin, H. et al. RNA-binding proteins in tumor progression. J. Hematol. Oncol. 13, 90 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Shi, H. et al. PCBP1 depletion promotes tumorigenesis through attenuation of p27(Kip1) mRNA stability and translation. J. Exp. Clin. Cancer Res. 37, 187 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Cobbold, L. C. et al. Upregulated c-myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB-1 and YB-1. Oncogene 29, 2884–2891 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Ho, J. J. D. et al. A network of RNA-binding proteins controls translation efficiency to activate anaerobic metabolism. Nat. Commun. 11, 2677 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Barbieri, I. et al. Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature 552, 126–131 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cheng, M. et al. The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network. Oncogene 38, 3667–3680 (2019).

    Article  CAS  PubMed  Google Scholar 

  108. Vu, L. P. et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat. Med. 23, 1369–1376 (2017). In this study, METTL3-dependent m6A modification is found to increase MYC and BCL2 mRNA translation and inhibit differentiation of human myeloid leukaemia cell lines.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Weng, H. et al. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification. Cell Stem Cell 22, 191–205.e199 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. Yang, D. D. et al. METTL3 promotes the progression of gastric cancer via targeting the MYC pathway. Front. Oncol. 10, 115 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Yuan, Y., Du, Y., Wang, L. & Liu, X. The M6A methyltransferase METTL3 promotes the development and progression of prostate carcinoma via mediating MYC methylation. J. Cancer 11, 3588–3595 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liu, J. et al. m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat. Cell Biol. 20, 1074–1083 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Leprivier, G., Rotblat, B., Khan, D., Jan, E. & Sorensen, P. H. Stress-mediated translational control in cancer cells. Biochim. Biophys. Acta 1849, 845–860 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Koromilas, A. E. Roles of the translation initiation factor eIF2α serine 51 phosphorylation in cancer formation and treatment. Biochim. Biophys. Acta 1849, 871–880 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Ivanov, P., Emara, M. M., Villen, J., Gygi, S. P. & Anderson, P. Angiogenin-induced tRNA fragments inhibit translation initiation. Mol. Cell 43, 613–623 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gerashchenko, M. V., Lobanov, A. V. & Gladyshev, V. N. Genome-wide ribosome profiling reveals complex translational regulation in response to oxidative stress. Proc. Natl Acad. Sci. USA 109, 17394–17399 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Shalgi, R. et al. Widespread regulation of translation by elongation pausing in heat shock. Mol. Cell 49, 439–452 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chen, C. W. & Tanaka, M. Genome-wide translation profiling by ribosome-bound tRNA Capture. Cell Rep. 23, 608–621 (2018).

    Article  CAS  PubMed  Google Scholar 

  119. Calvo, S. E., Pagliarini, D. J. & Mootha, V. K. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc. Natl Acad. Sci. USA 106, 7507–7512 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Johnstone, T. G., Bazzini, A. A. & Giraldez, A. J. Upstream ORFs are prevalent translational repressors in vertebrates. EMBO J. 35, 706–723 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Lu, P. D., Harding, H. P. & Ron, D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 167, 27–33 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269–11274 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bi, M. et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24, 3470–3481 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Clementi, E. et al. Persistent DNA damage triggers activation of the integrated stress response to promote cell survival under nutrient restriction. BMC Biol. 18, 36 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ye, J. et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 29, 2082–2096 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Quiros, P. M. et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J. Cell Biol. 216, 2027–2045 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. B’Chir, W. et al. The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 41, 7683–7699 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Pathria, G. et al. Translational reprogramming marks adaptation to asparagine restriction in cancer. Nat. Cell Biol. 21, 1590–1603 (2019). This study demonstrates that asparagine limitation promotes translational reprogramming downstream of MAPK–mTORC1–eIF4E signalling, enhancing ATF4 mRNA translation and survival of melanoma and pancreatic cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhou, J. et al. N6-Methyladenosine guides mRNA alternative translation during integrated stress response. Mol. Cell 69, 636–647.e637 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhou, J. et al. Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature 526, 591–594 (2015). This study, together with the studies by Meyer et al. (2015) and Coots et al. (2017), shows that m6A methylation in the 5′ UTR promotes cap-independent translation, especially during stress. This study also demonstrates that m6A methylation in the 5′ UTR of mRNAs is increased upon heat shock stress to promote cap-independent translation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Chen, H. H., Yu, H. I., Yang, M. H. & Tarn, W. Y. DDX3 activates CBC-eIF3-mediated translation of uORF-containing oncogenic mRNAs to promote metastasis in HNSCC. Cancer Res. 78, 4512–4523 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Starck, S. R. et al. Translation from the 5′ untranslated region shapes the integrated stress response. Science 351, aad3867 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Ho, J. J. D. et al. Oxygen-sensitive remodeling of central carbon metabolism by archaic eIF5B. Cell Rep. 22, 17–26 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sendoel, A. et al. Translation from unconventional 5′ start sites drives tumour initiation. Nature 541, 494–499 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Vagner, S. et al. Translation of CUG- but not AUG-initiated forms of human fibroblast growth factor 2 is activated in transformed and stressed cells. J. Cell Biol. 135, 1391–1402 (1996).

    Article  CAS  PubMed  Google Scholar 

  137. Meiron, M., Anunu, R., Scheinman, E. J., Hashmueli, S. & Levi, B. Z. New isoforms of VEGF are translated from alternative initiation CUG codons located in its 5′UTR. Biochem. Biophys. Res. Commun. 282, 1053–1060 (2001).

    Article  CAS  PubMed  Google Scholar 

  138. Trulley, P. et al. Alternative translation initiation generates a functionally distinct isoform of the stress-activated protein kinase MK2. Cell Rep. 27, 2859–2870 e2856 (2019).

    Article  CAS  PubMed  Google Scholar 

  139. Kearse, M. G. & Wilusz, J. E. Non-AUG translation: a new start for protein synthesis in eukaryotes. Genes Dev. 31, 1717–1731 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hann, S. R., Sloan-Brown, K. & Spotts, G. D. Translational activation of the non-AUG-initiated c-myc 1 protein at high cell densities due to methionine deprivation. Genes Dev. 6, 1229–1240 (1992).

    Article  CAS  PubMed  Google Scholar 

  141. Lee, S. et al. Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. Proc. Natl Acad. Sci. USA 109, E2424–E2432 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. & Weissman, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Shi, Y. et al. Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress. Oncogene 35, 1015–1024 (2016).

    Article  CAS  PubMed  Google Scholar 

  144. Galban, S. et al. RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha. Mol. Cell Biol. 28, 93–107 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Gu, L. et al. Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell 15, 363–375 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Dobbyn, H. C. et al. Regulation of BAG-1 IRES-mediated translation following chemotoxic stress. Oncogene 27, 1167–1174 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Chen, T. M. et al. hnRNPM induces translation switch under hypoxia to promote colon cancer development. EBioMedicine 41, 299–309 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Lee, A. S., Kranzusch, P. J., Doudna, J. A. & Cate, J. H. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature 536, 96–99 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lamper, A. M., Fleming, R. H., Ladd, K. M. & Lee, A. S. Y. A phosphorylation-regulated eIF3d translation switch mediates cellular adaptation to metabolic stress. Science 370, 853–856 (2020).

    Article  CAS  PubMed  Google Scholar 

  150. de la Parra, C. et al. A widespread alternate form of cap-dependent mRNA translation initiation. Nat. Commun. 9, 3068 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Torrent, M., Chalancon, G., de Groot, N. S., Wuster, A. & Madan Babu, M. Cells alter their tRNA abundance to selectively regulate protein synthesis during stress conditions. Sci Signal 11, eaat6409 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Saikia, M. et al. Codon optimality controls differential mRNA translation during amino acid starvation. RNA 22, 1719–1727 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Begley, U. et al. Trm9-catalyzed tRNA modifications link translation to the DNA damage response. Mol. Cell 28, 860–870 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Chan, C. T. et al. Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins. Nat. Commun. 3, 937 (2012).

    Article  PubMed  CAS  Google Scholar 

  155. Chan, C., Pham, P., Dedon, P. C. & Begley, T. J. Lifestyle modifications: coordinating the tRNA epitranscriptome with codon bias to adapt translation during stress responses. Genome Biol. 19, 228 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Endres, L. et al. Alkbh8 regulates selenocysteine-protein expression to protect against reactive oxygen species damage. PLoS ONE 10, e0131335 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Perillo, B. et al. ROS in cancer therapy: the bright side of the moon. Exp. Mol. Med. 52, 192–203 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Marine, J. C., Dawson, S. J. & Dawson, M. A. Non-genetic mechanisms of therapeutic resistance in cancer. Nat. Rev. Cancer 20, 743–756 (2020).

    Article  CAS  PubMed  Google Scholar 

  159. Gupta, P. B., Pastushenko, I., Skibinski, A., Blanpain, C. & Kuperwasser, C. Phenotypic plasticity: driver of cancer initiation, progression, and therapy resistance. Cell Stem Cell 24, 65–78 (2019).

    Article  CAS  PubMed  Google Scholar 

  160. Hoek, K. S. et al. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res. 68, 650–656 (2008).

    Article  CAS  PubMed  Google Scholar 

  161. Robichaud, N. et al. Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene 34, 2032–2042 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Smith, K. A. et al. Transforming growth factor-β1 induced epithelial mesenchymal transition is blocked by a chemical antagonist of translation factor eIF4E. Sci. Rep. 5, 18233 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Chaudhury, A. et al. CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT. Nat. Commun. 7, 13362 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Feng, Y. X. et al. Epithelial-to-mesenchymal transition activates PERK-eIF2α and sensitizes cells to endoplasmic reticulum stress. Cancer Discov. 4, 702–715 (2014).

    Article  CAS  PubMed  Google Scholar 

  165. Nagelkerke, A. et al. Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res. 15, R2 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Evdokimova, V. et al. Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition. Cancer Cell 15, 402–415 (2009). This is one of the first studies linking translational control to EMT. It describes the YB1-dependent promotion of the cap-independent translation initiation of SNAI1 and of other mRNAs encoding EMT-related proteins responsible for the invasiveness of breast epithelial cells.

    Article  CAS  PubMed  Google Scholar 

  167. Lin, X. et al. RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat. Commun. 10, 2065 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Chaudhury, A. et al. TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat. Cell Biol. 12, 286–293 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Hussey, G. S. et al. Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. Mol. Cell 41, 419–431 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Wurth, L. et al. UNR/CSDE1 drives a post-transcriptional program to promote melanoma invasion and metastasis. Cancer Cell 30, 694–707 (2016).

    Article  CAS  PubMed  Google Scholar 

  171. Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Signer, R. A. et al. The rate of protein synthesis in hematopoietic stem cells is limited partly by 4E-BPs. Genes Dev. 30, 1698–1703 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Zismanov, V. et al. Phosphorylation of eIF2alpha is a translational control mechanism regulating muscle stem cell quiescence and self-renewal. Cell Stem Cell 18, 79–90 (2016).

    Article  CAS  PubMed  Google Scholar 

  174. Blanco, S. et al. Stem cell function and stress response are controlled by protein synthesis. Nature 534, 335–340 (2016). This study demonstrates that global repression of translation concomitant with selective translation of specific transcripts functionally maintains stem cells in mouse normal skin or skin tumours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lamb, R. et al. Targeting tumor-initiating cells: eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction. Oncotarget 6, 4585–4601 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Samanta, S. et al. IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene 35, 1111–1121 (2016).

    Article  CAS  PubMed  Google Scholar 

  177. Samuels, T. J., Järvelin, A. I., Ish-Horowicz, D. & Davis, I. Imp/IGF2BP levels modulate individual neural stem cell growth and division through myc mRNA stability. eLife 9, e51529 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Dai, N. et al. IGF2BP2/IMP2-deficient mice resist obesity through enhanced translation of Ucp1 mRNA and other mRNAs encoding mitochondrial proteins. Cell Metab. 21, 609–621 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Degrauwe, N., Suvà, M. L., Janiszewska, M., Riggi, N. & Stamenkovic, I. IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer. Genes Dev. 30, 2459–2474 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Huang, H. et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat. Cell Biol. 20, 285–295 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Zhang, C. et al. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. Oncogene 39, 4507–4518 (2020).

    Article  CAS  PubMed  Google Scholar 

  182. Zhang, S. et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell 31, 591–606 e596 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Ladang, A. et al. Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. J. Exp. Med. 212, 2057–2075 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Mannoor, K., Shen, J., Liao, J., Liu, Z. & Jiang, F. Small nucleolar RNA signatures of lung tumor-initiating cells. Mol. Cancer 13, 104 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Zhang, L. et al. SNORA72 Activates the Notch1/c-Myc pathway to promote stemness transformation of ovarian cancer cells. Front. Cell Dev. Biol. 8, 583087 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Rambow, F., Marine, J. C. & Goding, C. R. Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities. Genes Dev. 33, 1295–1318 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Phung, B. et al. The X-linked DDX3X RNA helicase dictates translation reprogramming and metastasis in melanoma. Cell Rep. 27, 3573–3586.e3577 (2019).

    Article  CAS  PubMed  Google Scholar 

  188. Arozarena, I. & Wellbrock, C. Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat. Rev. Cancer 19, 377–391 (2019).

    Article  CAS  PubMed  Google Scholar 

  189. Anderson, N. M. & Simon, M. C. The tumor microenvironment. Curr. Biol. 30, R921–r925 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Lugano, R., Ramachandran, M. & Dimberg, A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol. Life Sci. 77, 1745–1770 (2020).

    Article  CAS  PubMed  Google Scholar 

  191. Braunstein, S. et al. A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol. Cell 28, 501–512 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Morfoisse, F. et al. Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1alpha-independent translation-mediated mechanism. Cell Rep. 6, 155–167 (2014).

    Article  CAS  PubMed  Google Scholar 

  193. Morfoisse, F. et al. Nucleolin promotes heat shock-associated translation of VEGF-D to promote tumor lymphangiogenesis. Cancer Res. 76, 4394–4405 (2016).

    Article  CAS  PubMed  Google Scholar 

  194. Clarke, C. J. et al. The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Curr. Biol. 26, 755–765 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Suo, J. et al. Int6 reduction activates stromal fibroblasts to enhance transforming activity in breast epithelial cells. Cell Biosci. 5, 10 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Araki, K. et al. Translation is actively regulated during the differentiation of CD8+ effector T cells. Nat. Immunol. 18, 1046–1057 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Scheu, S. et al. Activation of the integrated stress response during T helper cell differentiation. Nat. Immunol. 7, 644–651 (2006).

    Article  CAS  PubMed  Google Scholar 

  198. Wang, H. et al. Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation. Nat. Commun. 10, 1898 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Patel, C. H., Leone, R. D., Horton, M. R. & Powell, J. D. Targeting metabolism to regulate immune responses in autoimmunity and cancer. Nat. Rev. Drug Discov. 18, 669–688 (2019).

    Article  CAS  PubMed  Google Scholar 

  200. Puleston, D. J. et al. Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metab. 30, 352–363 e358 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ricciardi, S. et al. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling. Cell Metab. 28, 895–906 e895 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Chang, C. H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013). This study demonstrates that when aerobic glycolysis is inhibited, the glycolytic enzyme GAPDH can function as an RBP and can post-transcriptionally inhibit Ifng mRNA translation, coupling aerobic glycolysis with T cell effector functions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Hurst, K. E. et al. Remodeling translation primes CD8+ T-cell antitumor immunity. Cancer Immunol. Res. 8, 587–595 (2020).

    Article  CAS  PubMed  Google Scholar 

  204. Han, D. et al. Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells. Nature 566, 270–274 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Togashi, Y., Shitara, K. & Nishikawa, H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat. Rev. Clin. Oncol. 16, 356–371 (2019).

    Article  CAS  PubMed  Google Scholar 

  206. Bjur, E. et al. Distinct translational control in CD4+ T cell subsets. PLoS Genet. 9, e1003494 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Ansa-Addo, E. A. et al. Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling. J. Clin. Invest. 127, 1321–1337 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Amobi, A., Qian, F., Lugade, A. A. & Odunsi, K. Tryptophan catabolism and cancer immunotherapy targeting IDO mediated immune suppression. Adv. Exp. Med. Biol. 1036, 129–144 (2017).

    Article  CAS  PubMed  Google Scholar 

  209. Bartok, O. et al. Anti-tumour immunity induces aberrant peptide presentation in melanoma. Nature 590, 332–337 (2021). This study interestingly shows that IDO1-dependent tryptophan depletion, induced by INFγ, interferes with the initiation of mRNA translation and results in ribosomal frameshifting, leading to aberrant peptide presentation and to the recognition of melanoma cells by T cells.

    Article  CAS  PubMed  Google Scholar 

  210. Starck, S. R. & Shastri, N. Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance. Immunol. Rev. 272, 8–16 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Chen, J. et al. Pervasive functional translation of noncanonical human open reading frames. Science 367, 1140–1146 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Cerezo, M. et al. Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma. Nat. Med. 24, 1877–1886 (2018). This article reveals that eIF4F-mediated control of STAT1 mRNA translation regulates the expression of IFNγ-induced PDL1 in melanoma.

    Article  CAS  PubMed  Google Scholar 

  213. Suresh, S. et al. eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer. Nat. Cancer 1, 533–545 (2020). This article, together with the article by Xu et al. (2019), describes that uORF-mediated translational repression is a mechanism of translational control of the mRNA encoding PDL1. This study also shows that activation of the ISR allows translational upregulation of PDL1 mRNA dependent on eIF5B and the bypass of inhibitory uORF.

    Article  PubMed  PubMed Central  Google Scholar 

  214. Xu, Y. et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat. Med. 25, 301–311 (2019). This article, together with the article by Suresh et al. (2020), describes that uORF-mediated translational repression is a mechanism of translational control of the mRNA encoding PDL1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Huang, C. I. et al. eIF4E and 4EBP1 are prognostic markers of head and neck squamous cell carcinoma recurrence after definitive surgery and adjuvant radiotherapy. PLoS ONE 14, e0225537 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Li, Z. et al. Inhibiting the MNK-eIF4E-β-catenin axis increases the responsiveness of aggressive breast cancer cells to chemotherapy. Oncotarget 8, 2906–2915 (2017).

    Article  PubMed  Google Scholar 

  217. Sridharan, S. et al. Targeting of the eukaryotic translation initiation factor 4 A against breast cancer stemness. Front. Oncol. 9, 1311 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Wangpaichitr, M. et al. Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur. J. Pharmacol. 591, 124–127 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Liang, S. Q. et al. mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer. Oncogene 38, 622–636 (2019).

    Article  CAS  PubMed  Google Scholar 

  220. David-West, G., Ernlund, A., Gadi, A. & Schneider, R. J. mTORC1/2 inhibition re-sensitizes platinum-resistant ovarian cancer by disrupting selective translation of DNA damage and survival mRNAs. Oncotarget 9, 33064–33076 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  221. Adesso, L. et al. Gemcitabine triggers a pro-survival response in pancreatic cancer cells through activation of the MNK2/eIF4E pathway. Oncogene 32, 2848–2857 (2013).

    Article  CAS  PubMed  Google Scholar 

  222. Liwak, U. et al. Loss of PDCD4 contributes to enhanced chemoresistance in Glioblastoma multiforme through de-repression of Bcl-xL translation. Oncotarget 4, 1365–1372 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Wang, D. et al. Programmed cell death factor 4 enhances the chemosensitivity of colorectal cancer cells to Taxol. Oncol. Lett. 18, 1402–1408 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Bourguignon, L. Y., Spevak, C. C., Wong, G., Xia, W. & Gilad, E. Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J. Biol. Chem. 284, 26533–26546 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Vaysse, C. et al. Key contribution of eIF4H-mediated translational control in tumor promotion. Oncotarget 6, 39924–39940 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Nussinov, R., Tsai, C. J. & Jang, H. A new view of pathway-driven drug resistance in tumor proliferation. Trends Pharmacol. Sci. 38, 427–437 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Boussemart, L. et al. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature 513, 105–109 (2014). This study describes that resistance of melanoma cells to combined BRAF and MEK inhibition is associated with regulated formation of the eIF4F complex. A combination of BRAF and eIF4F inhibition overcomes resistance.

    Article  CAS  PubMed  Google Scholar 

  228. Zindy, P. et al. Formation of the eIF4F translation-initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors. Cancer Res. 71, 4068–4073 (2011).

    Article  CAS  PubMed  Google Scholar 

  229. Gong, C. et al. Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer. Oncogene 39, 3206–3217 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Fagan, D. H. et al. Acquired tamoxifen resistance in MCF-7 breast cancer cells requires hyperactivation of eIF4F-mediated translation. Horm. Cancer 8, 219–229 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Geter, P. A. et al. Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming. Genes Dev. 31, 2235–2249 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Adjibade, P. et al. Sorafenib, a multikinase inhibitor, induces formation of stress granules in hepatocarcinoma cells. Oncotarget 6, 43927–43943 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Pathria, G. et al. Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J. 37, e99735 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  234. Ali, M. et al. Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. Nat. Commun. 8, 15617 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Okamoto, M. et al. tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells. PLoS Genet. 10, e1004639 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Yan, F. et al. A dynamic N6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors. Cell Res. 28, 1062–1076 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Lin, Z. et al. RNA m6A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy. EMBO J. 39, e103181 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Badawi, A. et al. Inhibition of IRES-dependent translation of caspase-2 by HuR confers chemotherapeutic drug resistance in colon carcinoma cells. Oncotarget 9, 18367–18385 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Heise, T. et al. The La protein counteracts cisplatin-induced cell death by stimulating protein synthesis of anti-apoptotic factor Bcl2. Oncotarget 7, 29664–29676 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Shi, Y. et al. Ribosomal proteins S13 and L23 promote multidrug resistance in gastric cancer cells by suppressing drug-induced apoptosis. Exp. Cell Res. 296, 337–346 (2004).

    Article  CAS  PubMed  Google Scholar 

  241. Bram Ednersson, S. et al. Expression of ribosomal and actin network proteins and immunochemotherapy resistance in diffuse large B cell lymphoma patients. Br. J. Haematol. 181, 770–781 (2018).

    Article  CAS  PubMed  Google Scholar 

  242. Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Chaffer, C. L. et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl Acad. Sci. USA 108, 7950–7955 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Pisco, A. O. & Huang, S. Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: ‘What does not kill me strengthens me’. Br. J. Cancer 112, 1725–1732 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Sharma, A. et al. Non-genetic intra-tumor heterogeneity is a major predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in lung tumors. Cell Rep. 29, 2164–2174.e2165 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Rambow, F. et al. Toward minimal residual disease-directed therapy in melanoma. Cell 174, e819 (2018).

    Article  CAS  Google Scholar 

  247. Sánchez-Danés, A. et al. A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy. Nature 562, 434–438 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19, 39–56 (2020).

    Article  CAS  PubMed  Google Scholar 

  249. Shen, S. et al. An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells. Nat. Commun. 10, 5713 (2019). This article describes a mechanism of reversible translational reprogramming underlying the drug-persistent state of melanoma cells. It reveals that a subset of m6A-modified mRNAs are actively translated in an eIF4A-dependent manner.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Hata, A. N. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262–269 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Shaffer, S. M. et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 546, 431–435 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Heinonen, M. et al. Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res. 65, 2157–2161 (2005).

    Article  CAS  PubMed  Google Scholar 

  253. Zhao, S. et al. High expression of Y-box-binding protein 1 correlates with poor prognosis and early recurrence in patients with small invasive lung adenocarcinoma. Onco Targets Ther. 9, 2683–2692 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Carter, J. H. et al. Phosphorylation of eIF4E serine 209 is associated with tumour progression and reduced survival in malignant melanoma. Br. J. Cancer 114, 444–453 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00462943 (2010).

  256. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01675128 (2014).

  257. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04092673 (2021).

  258. Sonenberg, N. & Hinnebusch, A. G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Wendel, H. G. et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332–337 (2004).

    Article  CAS  PubMed  Google Scholar 

  260. Gingras, A. C. et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 13, 1422–1437 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Gingras, A. C. et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev. 15, 2852–2864 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Bah, A. et al. Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch. Nature 519, 106–109 (2015).

    Article  CAS  PubMed  Google Scholar 

  263. Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H. & Sabatini, D. M. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl Acad. Sci. USA 95, 1432–1437 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Dorrello, N. V. et al. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314, 467–471 (2006).

    Article  CAS  PubMed  Google Scholar 

  265. Raught, B. et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 23, 1761–1769 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Ueda, T., Watanabe-Fukunaga, R., Fukuyama, H., Nagata, S. & Fukunaga, R. Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol. Cell Biol. 24, 6539–6549 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21–35 (2011).

    Article  CAS  PubMed  Google Scholar 

  269. Inoki, K., Li, Y., Xu, T. & Guan, K. L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829–1834 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    Article  CAS  PubMed  Google Scholar 

  271. Gomez, E., Mohammad, S. S. & Pavitt, G. D. Characterization of the minimal catalytic domain within eIF2B: the guanine-nucleotide exchange factor for translation initiation. EMBO J. 21, 5292–5301 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Huang, X. B. et al. MNK1 inhibitor CGP57380 overcomes mTOR inhibitor-induced activation of eIF4E: the mechanism of synergic killing of human T-ALL cells. Acta Pharmacol. Sin. 39, 1894–1901 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Wen, Q. et al. CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway. Oncotarget 7, 27787–27801 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  274. Zhang, W. et al. Inhibiting MNK selectively targets cervical cancer via suppressing eIF4E-mediated β-catenin activation. Am. J. Med. Sci. 358, 227–234 (2019).

    Article  PubMed  Google Scholar 

  275. Duffy, A. G. et al. Modulation of tumor eIF4E by antisense inhibition: a phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer. Int. J. Cancer 139, 1648–1657 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Ahmad, Z. et al. Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma. Cancer Chemother. Pharmacol. 85, 425–432 (2020).

    Article  CAS  PubMed  Google Scholar 

  277. Shen, L. & Pelletier, J. Selective targeting of the DEAD-box RNA helicase eukaryotic initiation factor (eIF) 4A by natural products. Nat. Prod. Rep. 37, 609–616 (2020).

    Article  CAS  PubMed  Google Scholar 

  278. Zhang, X. et al. Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas. Leukemia 34, 138–150 (2020).

    Article  CAS  PubMed  Google Scholar 

  279. Kong, T. et al. eIF4A inhibitors suppress cell-cycle feedback response and acquired resistance to CDK4/6 inhibition in cancer. Mol. Cancer Ther. 18, 2158–2170 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Darini, C. et al. An integrated stress response via PKR suppresses HER2+cancers and improves trastuzumab therapy. Nat. Commun. 10, 2139 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  281. Jeon, Y. J. et al. Salubrinal-mediated upregulation of eIF2alpha phosphorylation increases doxorubicin sensitivity in MCF-7/ADR cells. Mol. Cell 39, 129–135 (2016).

    Article  CAS  Google Scholar 

  282. Burwick, N. et al. The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma. Leuk. Res. 55, 23–32 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Keysar, S. B. et al. Inhibiting translation elongation with SVC112 suppresses cancer stem cells and inhibits growth in head and neck squamous carcinoma. Cancer Res. 80, 1183–1198 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Institut Curie, CNRS, INSERM and Ligue Nationale Contre le Cancer Equipe Labellisée for funding. L.F. was funded by a postdoctoral fellowship from Fondation ARC.

Author information

Authors and Affiliations

  1. Institut Curie, PSL Research University, CNRS UMR3348, INSERM U1278, Orsay, France

    Lucilla Fabbri, Alina Chakraborty & Stéphan Vagner

  2. Université Paris Sud, Université Paris-Saclay, CNRS UMR3348, INSERM U1278, Orsay, France

    Lucilla Fabbri, Alina Chakraborty & Stéphan Vagner

  3. Equipe Labellisée Ligue Nationale Contre le Cancer, Orsay, France

    Lucilla Fabbri, Alina Chakraborty & Stéphan Vagner

  4. INSERM U981, Gustave Roussy Cancer Campus, Villejuif, France

    Caroline Robert

  5. Université Paris-Sud, Université Paris-Saclay, Kremlin-Bicêtre, France

    Caroline Robert

  6. Dermato-Oncology, Gustave Roussy Cancer Campus, Villejuif, France

    Caroline Robert & Stéphan Vagner

Authors
  1. Lucilla Fabbri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alina Chakraborty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caroline Robert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stéphan Vagner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.F. and A.C. researched data for the article. All authors contributed substantially to discussion of the content. L.F., A.C. and S.V. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Stéphan Vagner.

Ethics declarations

Competing interests

C.R. is an occasional consultant for Bristol Myers Squibb, MSD, Novartis, Sanofi, AstraZeneca, Pfizer, Roche and Pierre Fabre. C.R. and S.V. are scientific founders of Aglaia Therapeutics. L.F. and A.C. declare no competing interests.

Additional information

Peer review information

Nature Reviews Cancer thanks F. Gebauer, K. De Keersmaecker and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

RNA-binding proteins

(RBPs). Proteins that bind single-stranded or double-stranded RNA through specific structural motifs to regulate RNA metabolism and function. Some proteins capable of binding RNA lack conventional RNA-binding domains.

Codon usage

The frequency with which synonymous codons (different codons that encode the same amino acid) occur within a genome.

Upstream open reading frames

(uORFs). Cis-acting elements within the 5′ leader sequence of transcripts with an initiation codon in frame with a termination codon that differs from that associated with the main ORF.

40S ribosomal subunit

Smaller subunit of eukaryotic ribosomes (also known as 80S ribosomes) consisting of 33 proteins and an 18S rRNA. It binds initiation factors that facilitate scanning of mRNAs and the initiation of protein synthesis.

Internal ribosome entry site (IRES) elements

Cis-acting regions on transcripts that promote the cap-independent, internal initiation of translation. IRES elements are classified on the basis of conserved RNA motifs that impact RNA–protein interactions to drive IRES-mediated translation.

Kozak sequence

Optimal mRNA sequence surrounding the AUG start codon and defined as 5′-(A/G)CCAUGG-3′.

N 6-Methyladenosine (m6A) methylation

The reversible methylation of adenine at the sixth position (N-methyladenosine) on RNAs that contributes to the post-transcriptional regulation of gene expression in development and in disease.

Synonymous codons

Different codons (nucleotide triplet combinations) mediating the insertion of the same amino acid into a polypeptide chain.

U34 wobble position

Uridines at position 34 (U34) (also known as the wobble position) located in the anticodon loop of tRNA that can contain modifications allowing more flexible and non-Watson–Crick codon–anticodon base pairing.

Programmed −1 ribosomal frameshifting

Controlled slippage of the translating ribosome that shifts the reading frame by one base in the 5′ direction during translation.

Integrated stress response

(ISR). A cellular pathway induced by various stresses that cause one of the four eukaryotic initiation factor 2α (eIF2α) kinases to phosphorylate eIF2, leading to a global decrease in protein synthesis but the induction of specific genes that promote the restoration of cellular homeostasis.

Stress granules

Stress induced, membraneless assemblies of non-translating messenger ribonucleoproteins in the cytoplasm that sequester specific mRNAs stalled in translation in response to stress.

tRNA fragmentation

Cleavage of tRNA to produce tRNA-derived fragments. The stress-induced cleavage of some tRNAs at the anticodon loop produces tRNA fragments that globally inhibit translation elongation.

Small nucleolar RNAs

(snoRNAs). Metabolically stable, 60–300-nucleotide-long RNAs abundant in the nucleolus and involved in the post-transcriptional modification (2′-O-ribose methylation or pseudouridylation) of ribosomal RNAs and other cellular RNAs.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fabbri, L., Chakraborty, A., Robert, C. et al. The plasticity of mRNA translation during cancer progression and therapy resistance. Nat Rev Cancer 21, 558–577 (2021). https://doi.org/10.1038/s41568-021-00380-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-021-00380-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer