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:

RNA editing-dependent epitranscriptome diversity in cancer stem cells

Nature Reviews Cancer volume 17, pages 381–392 (2017)Cite this article

Subjects

Key Points

  • Methylation of RNA at N6-methyladenosine (m6A) has been identified in humans, viruses and mice and has been linked to several diseases.

  • m6A plays an important role in pluripotency and differentiation and has therefore been associated with cancer development; it can promote the translation of several oncogenes.

  • Malignant adenosine-to-inosine RNA editing controls the self-renewal of cancer stem cells (CSCs), and raises the possibility that targeting this pathway may provide a new strategy for eliminating CSCs.

  • RNA splicing disruption promotes generation of aberrant splice isoforms in pre-malignant and malignant haematopoietic disorders and is a key therapeutic vulnerability in a growing number of human malignancies.

  • Therapeutic splicing modulation has the potential to target bulk tumour cells as well as self-renewing CSCs that contribute to disease progression and relapse.

Abstract

Cancer stem cells (CSCs) can regenerate all facets of a tumour as a result of their stem cell-like capacity to self-renew, survive and become dormant in protective microenvironments. CSCs evolve during tumour progression in a manner that conforms to Charles Darwin's principle of natural selection. Although somatic DNA mutations and epigenetic alterations promote evolution, post-transcriptional RNA modifications together with RNA binding protein activity (the 'epitranscriptome') might also contribute to clonal evolution through dynamic determination of RNA function and gene expression diversity in response to environmental stimuli. Deregulation of these epitranscriptomic events contributes to CSC generation and maintenance, which governs cancer progression and drug resistance. In this Review, we discuss the role of malignant RNA processing in CSC generation and maintenance, including mechanisms of RNA methylation, RNA editing and RNA splicing, and the functional consequences of their aberrant regulation in human malignancies. Finally, we highlight the potential of these events as novel CSC biomarkers as well as therapeutic targets.

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

Figure 1: Epitranscriptome regulation contributes to cancer stem cell generation.
Figure 2: Consequences of RNA editing by ADAR.
Figure 3: Translational control by MSI2 directs normal and leukaemic stem cell function.
Figure 4: RNA processing in normal and malignant haematopoiesis.

Similar content being viewed by others

References

  1. Darwin, C. On the Origin of Species by Means of Natural Selection (John Murray, 1859).

    Google Scholar 

  2. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8, 755–768 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Saletore, Y. et al. The birth of the epitranscriptome: deciphering the function of RNA modifications. Genome Biol. 13, 175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chadwick, L. H. The NIH Roadmap Epigenomics Program data resource. Epigenomics 4, 317–324 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Dai, B. & Rasmussen, T. P. Global epiproteomic signatures distinguish embryonic stem cells from differentiated cells. Stem Cells 25, 2567–2574 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Jiang, Q. et al. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc. Natl Acad. Sci. USA 110, 1041–1046 (2013). This study showed for the first time that A-to-I RNA editing by ADAR1 is associated with leukaemic transformation and is required for CSC self-renewal capacity.

    Article  CAS  PubMed  Google Scholar 

  8. Johnson, J. M. et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 302, 2141–2144 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Pan, Q. et al. Alternative splicing of conserved exons is frequently species-specific in human and mouse. Trends Genet. 21, 73–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Crews, L. A. et al. RNA splicing modulation selectively impairs leukemia stem cell maintenance in secondary human AML. Cell Stem Cell 19, 599–612 (2016). This study was the first to show that small-molecule splicing modulators can selectively target self-renewing CSCs while sparing normal HSCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012). This paper describes that silencing of m6A methyltranferase affects gene expression as well as alternative splicing patterns, resulting in modulation of p53 and indicating a role for m6A in gene expression regulation.

    Article  CAS  PubMed  Google Scholar 

  12. Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012). By uncovering an association between m6A residues and miRNA-binding sites in 3′-UTRs this study provided insight into the epigenetic regulation of the mammalian transcriptome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. De Los Angeles, A. et al. Hallmarks of pluripotency. Nature 525, 469–478 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Licht, K. & Jantsch, M. F. Rapid and dynamic transcriptome regulation by RNA editing and RNA modifications. J. Cell Biol. 213, 15–22 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee, T. I. & Young, R. A. Transcriptional regulation and its misregulation in disease. Cell 152, 1237–1251 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gonda, T. J. & Ramsay, R. G. Directly targeting transcriptional dysregulation in cancer. Nat. Rev. Cancer 15, 686–694 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Perry, R. P. & Kelley, D. E. Existence of methylated messenger-RNA in mouse L cells. Cell 1, 37–42 (1974).

    Article  CAS  Google Scholar 

  20. Desrosiers, R., Friderici, K. & Rottman, F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl Acad. Sci. USA 71, 3971–3975 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Basanta-Sanchez, M., Temple, S., Ansari, S. A., D'Amico, A. & Agris, P. F. Attomole quantification and global profile of RNA modifications: epitranscriptome of human neural stem cells. Nucleic Acids Res. 44, e26 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Batista, P. J. et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moss, B., Gershowitz, A., Stringer, J. R., Holland, L. E. & Wagner, E. K. 5′-terminal and internal methylated nucleosides in herpes simplex virus type 1 mRNA. J. Virol. 23, 234–239 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Desrosiers, R. C., Friderici, K. H. & Rottman, F. M. Characterization of Novikoff hepatoma mRNA methylation and heterogeneity in the methylated 5′ terminus. Biochemistry 14, 4367–4374 (1975).

    Article  CAS  PubMed  Google Scholar 

  25. Iwanami, Y. & Brown, G. M. Methylated bases of transfer ribonucleic acid from HeLa and L cells. Arch. Biochem. Biophys. 124, 472–482 (1968).

    Article  CAS  PubMed  Google Scholar 

  26. Liu, N. et al. Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA 19, 1848–1856 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Keller, L. et al. The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J. Alzheimers Dis. 23, 461–469 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Chen, T. et al. m6A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 16, 289–301 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Geula, S. et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347, 1002–1006 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Niu, Y. et al. N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function. Genomics Proteomics Bioinformatics 11, 8–17 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Li, Z. et al. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell 31, 127–141 (2017). This is a seminal study of the functional importance of m6A methylation in cancer, its impact on leukaemogenesis and ultimately its role in drug response.

    Article  CAS  PubMed  Google Scholar 

  32. 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 is a novel report of METTL3 and its involvement in human cancer by promoting translation of oncogenes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ben-Porath, I. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40, 499–507 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hu, T. et al. Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res. 68, 6533–6540 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Yu, F. et al. Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene 30, 2161–2172 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Leis, O. et al. Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 31, 1354–1365 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Iv Santaliz-Ruiz, L. E., Xie, X., Old, M., Teknos, T. N. & Pan, Q. Emerging role of nanog in tumorigenesis and cancer stem cells. Int. J. Cancer 135, 2741–2748 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Zipeto, M. A., Jiang, Q., Melese, E. & Jamieson, C. H. RNA rewriting, recoding, and rewiring in human disease. Trends Mol. Med. 21, 549–559 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Anadon, C. et al. Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis. Oncogene 35, 4407–4413 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Zipeto, M. A. et al. ADAR1 activation drives leukemia stem cell self-renewal by impairing let-7 biogenesis. Cell Stem Cell 19, 177–191 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mannion, N. M. et al. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 9, 1482–1494 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liddicoat, B. J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Strout, M. P., Marcucci, G., Bloomfield, C. D. & Caligiuri, M. A. The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia. Proc. Natl Acad. Sci. USA 95, 2390–2395 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Elliott, B., Richardson, C. & Jasin, M. Chromosomal translocation mechanisms at intronic alu elements in mammalian cells. Mol. Cell 17, 885–894 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Jeffs, A. R., Benjes, S. M., Smith, T. L., Sowerby, S. J. & Morris, C. M. The BCR gene recombines preferentially with Alu elements in complex BCR–ABL translocations of chronic myeloid leukaemia. Hum. Mol. Genet. 7, 767–776 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Guarnerio, J. et al. Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations. Cell 165, 289–302 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Osenberg, S. et al. Alu sequences in undifferentiated human embryonic stem cells display high levels of A-to-I RNA editing. PLoS ONE 5, e11173 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Guo, J. et al. Unraveling molecular effects of ADAR1 overexpression in HEK293T cells by label-free quantitative proteomics. Cell Cycle 15, 1591–1601 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809–813 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Fumagalli, D. et al. Principles governing A-to-I RNA editing in the breast cancer transcriptome. Cell Rep. 13, 277–289 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Qi, L., Chan, T. H., Tenen, D. G. & Chen, L. RNA editome imbalance in hepatocellular carcinoma. Cancer Res. 74, 1301–1306 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Qin, Y. R. et al. Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma. Cancer Res. 74, 840–851 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Wang, Q., Khillan, J., Gadue, P. & Nishikura, K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290, 1765–1768 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Hartner, J. C., Walkley, C. R., Lu, J. & Orkin, S. H. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat. Immunol. 10, 109–115 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Abrahamsson, A. E. et al. Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proc. Natl Acad. Sci. USA 106, 3925–3929 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chen, L. et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat. Med. 19, 209–216 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Han, L. et al. The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 28, 515–528 (2015). By profiling genome-wide A-to-I RNA editing events in 17 cancer types, the authors report here that nonsynomymous RNA editing is associated with tumour cell viability and drug sensitivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kawahara, Y. et al. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315, 1137–1140 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pfeffer, S. et al. Identification of microRNAs of the herpesvirus family. Nat. Methods 2, 269–276 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Yang, W. et al. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat. Struct. Mol. Biol. 13, 13–21 (2006). This article shows that A-to-I editing of pri-miRNA-142 by ADAR1 and ADAR2 suppresses DROSHA processing and mature miRNA production, revealing a role for RNA editing in miRNA biogenesis.

    Article  CAS  PubMed  Google Scholar 

  61. Solomon, O. et al. Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR). RNA 19, 591–604 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ota, H. et al. ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing. Cell 153, 575–589 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen, T. et al. ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner. Cell Res. 25, 459–476 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lechman, E. R. et al. miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell 29, 602–606 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Heale, B. S. et al. Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO J. 28, 3145–3156 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wulff, B. E. & Nishikura, K. Modulation of microRNA expression and function by ADARs. Curr. Top. Microbiol. Immunol. 353, 91–109 (2012).

    CAS  PubMed  Google Scholar 

  67. Nishikura, K. A-To-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Lagos-Quintana, M. et al. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Isobe, T. et al. miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. eLife 3, e01977 (2014).

    Article  PubMed Central  Google Scholar 

  70. Garofalo, M. & Croce, C. M. Role of microRNAs in maintaining cancer stem cells. Adv. Drug Deliv. Rev. 81, 53–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Zhou, J., Ng, S. B. & Chng, W. J. LIN28/LIN28B: an emerging oncogenic driver in cancer stem cells. Int. J. Biochem. Cell Biol. 45, 973–978 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Kiran, A. & Baranov, P. V. DARNED: a database of RNA editing in humans. Bioinformatics 26, 1772–1776 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Yulug, I. G., Yulug, A. & Fisher, E. M. The frequency and position of Alu repeats in cDNAs, as determined by database searching. Genomics 27, 544–548 (1995).

    Article  CAS  PubMed  Google Scholar 

  75. Zhang, Z. & Carmichael, G. G. The fate of dsRNA in the nucleus: a p54nrb-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 106, 465–475 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Scadden, A. D. The RISC subunit Tudor-SN binds to hyper-edited double-stranded RNA and promotes its cleavage. Nat. Struct. Mol. Biol. 12, 489–496 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Borchert, G. M. et al. Adenosine deamination in human transcripts generates novel microRNA binding sites. Hum. Mol. Genet. 18, 4801–4807 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang, L., Yang, C. S., Varelas, X. & Monti, S. Altered RNA editing in 3′ UTR perturbs microRNA-mediated regulation of oncogenes and tumor-suppressors. Sci. Rep. 6, 23226 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bahn, J. H. et al. Genomic analysis of ADAR1 binding and its involvement in multiple RNA processing pathways. Nat. Commun. 6, 6355 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Mayr, C. & Bartel, D. P. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Morris, A. R., Mukherjee, N. & Keene, J. D. Systematic analysis of posttranscriptional gene expression. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 162–180 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Ye, J. & Blelloch, R. Regulation of pluripotency by RNA binding proteins. Cell Stem Cell 15, 271–280 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Okano, H., Imai, T. & Okabe, M. Musashi: a translational regulator of cell fate. J. Cell Sci. 115, 1355–1359 (2002).

    CAS  PubMed  Google Scholar 

  84. Ma, Z. et al. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat. Genet. 28, 220–221 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Xiao, N. et al. Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress. Blood 119, 4898–4907 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. King, C. E. et al. LIN28B promotes colon cancer progression and metastasis. Cancer Res. 71, 4260–4268 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Peng, S., Maihle, N. J. & Huang, Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene 29, 2153–2159 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Zhang, W. C. et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148, 259–272 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Yang, X. et al. Double-negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells. Cancer Res. 70, 9463–9472 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nakamura, M., Okano, H., Blendy, J. A. & Montell, C. Musashi, a neural RNA-binding protein required for Drosophila adult external sensory organ development. Neuron 13, 67–81 (1994).

    Article  CAS  PubMed  Google Scholar 

  91. Fox, R. G., Park, F. D., Koechlein, C. S., Kritzik, M. & Reya, T. Musashi signaling in stem cells and cancer. Annu. Rev. Cell Dev. Biol. 31, 249–267 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Ito, T. et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466, 765–768 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fox, R. G. et al. Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 534, 407–411 (2016). These authors showed that MSI2 expression can identify pancreatic CSCs, and that antisense oligonucleotides against MSI effectively block pancreatic cancer invasion and growth.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Park, S. M. et al. Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program. J. Clin. Invest. 125, 1286–1298 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Kwon, H. Y. et al. Tetraspanin 3 is required for the development and propagation of acute myelogenous leukemia. Cell Stem Cell 17, 152–164 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sakakibara, S. et al. RNA-binding protein Musashi family: roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation. Proc. Natl Acad. Sci. USA 99, 15194–15199 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Imai, T. et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol. Cell. Biol. 21, 3888–3900 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kharas, M. G. et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat. Med. 16, 903–908 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jamieson, C. H. et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657–667 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Kawahara, H. et al. Neural RNA-binding protein Musashi1 inhibits translation initiation by competing with eIF4G for PABP. J. Cell Biol. 181, 639–653 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. DeBoever, C. et al. Transcriptome sequencing reveals potential mechanism of cryptic 3′ splice site selection in SF3B1-mutated cancers. PLoS Comput. Biol. 11, e1004105 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Barrett, C. L. et al. Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy. Proc. Natl Acad. Sci. USA 112, E3050–E3057 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Goff, D. J. et al. A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition. Cell Stem Cell 12, 316–328 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Holm, F. et al. Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal. Proc. Natl Acad. Sci. USA 112, 15444–15449 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Crews, L. A. & Jamieson, C. H. Selective elimination of leukemia stem cells: hitting a moving target. Cancer Lett. 338, 15–22 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Pang, W. W. et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl Acad. Sci. USA 108, 20012–20017 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dolatshad, H. et al. Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia 29, 1092–1103 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Adamia, S. et al. A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets. Clin. Cancer Res. 20, 1135–1145 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Han, H. et al. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature 498, 241–245 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sebestyen, E. et al. Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks. Genome Res. 26, 732–744 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lasho, T. L. et al. SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients. Leukemia 26, 1135–1137 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Wang, L. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497–2506 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Yoshida, K. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64–69 (2011). This is one of the first seminal papers identifying DNA mutations occurring in splicing regulatory genes in pre-malignant haematopoietic disorders.

    Article  CAS  PubMed  Google Scholar 

  114. Hahn, C. N. & Scott, H. S. Spliceosome mutations in hematopoietic malignancies. Nat. Genet. 44, 9–10 (2011).

    Article  PubMed  CAS  Google Scholar 

  115. Thol, F. et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 119, 3578–3584 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Zhang, S. J. et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood 119, 4480–4485 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Malcovati, L. et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 118, 6239–6246 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Papaemmanuil, E. et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 365, 1384–1395 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lee, S. C. et al. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat. Med. 22, 672–678 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Adler, A. S. et al. An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth. Genes Dev. 28, 1068–1084 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Jiang, L. et al. Genomic landscape survey identifies SRSF1 as a key oncodriver in small cell lung cancer. PLoS Genet. 12, e1005895 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Golan-Gerstl, R. et al. Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma. Cancer Res. 71, 4464–4472 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Hsu, T. Y. et al. The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 525, 384–388 (2015). This work describes a non-mutation-dependent mechanism of spliceosome disruption in solid tumours that functionally sensitizes tumour cells to treatment with small-molecule splicing modulatory compounds.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kashyap, M. K. et al. Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B. Haematologica 100, 945–954 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Salton, M. et al. Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing. Nat. Commun. 6, 7103 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Raitskin, O., Cho, D. S., Sperling, J., Nishikura, K. & Sperling, R. RNA editing activity is associated with splicing factors in lnRNP particles: the nuclear pre-mRNA processing machinery. Proc. Natl Acad. Sci. USA 98, 6571–6576 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shefer, K., Sperling, J. & Sperling, R. The supraspliceosome — a multi-task machine for regulated pre-mRNA processing in the cell nucleus. Comput. Struct. Biotechnol. J. 11, 113–122 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Rueter, S. M., Dawson, T. R. & Emeson, R. B. Regulation of alternative splicing by RNA editing. Nature 399, 75–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Beghini, A. et al. RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. Hum. Mol. Genet. 9, 2297–2304 (2000).

    Article  CAS  PubMed  Google Scholar 

  130. Lev-Maor, G. et al. RNA-editing-mediated exon evolution. Genome Biol. 8, R29 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lev-Maor, G. et al. Intronic Alus influence alternative splicing. PLoS Genet. 4, e1000204 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Licht, K., Kapoor, U., Mayrhofer, E. & Jantsch, M. F. Adenosine to inosine editing frequency controlled by splicing efficiency. Nucleic Acids Res. 44, 6398–6408 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tariq, A. et al. RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation. Nucleic Acids Res. 41, 2581–2593 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Dvinge, H., Kim, E., Abdel-Wahab, O. & Bradley, R. K. RNA splicing factors as oncoproteins and tumour suppressors. Nat. Rev. Cancer 16, 413–430 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mizrahi, R. A., Schirle, N. T. & Beal, P. A. Potent and selective inhibition of A-to-I RNA editing with 2′-O-methyl/locked nucleic acid-containing antisense oligoribonucleotides. ACS Chem. Biol. 8, 832–839 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Schirle, N. T., Goodman, R. A., Krishnamurthy, M. & Beal, P. A. Selective inhibition of ADAR2-catalyzed editing of the serotonin 2c receptor pre-mRNA by a helix-threading peptide. Org. Biomol. Chem. 8, 4898–4904 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Crews, L. A. et al. An RNA editing fingerprint of cancer stem cell reprogramming. J. Transl Med. 13, 52 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Ramaswami, G. & Li, J. B. RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res. 42, D109–D113 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994). This is the first study to identify a self-renewing CSC population in haematological malignancies.

    Article  CAS  PubMed  Google Scholar 

  140. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hemmati, H. D. et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl Acad. Sci. USA 100, 15178–15183 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kim, C. F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. O'Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J. & Maitland, N. J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Szotek, P. P. et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. Proc. Natl Acad. Sci. USA 103, 11154–11159 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Takebe, N. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. 12, 445–464 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. LaBarge, M. A. The difficulty of targeting cancer stem cell niches. Clin. Cancer Res. 16, 3121–3129 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the inspiration and support of their patients and their professional colleagues. This work was supported by the Moores Foundation, California Institute for Regenerative Medicine (CIRM) grants (RN2-00910-1, DR1-01430 and RS1-00228-1); CIRM Training Grant (TG2-01154); National Institutes of Health (NIH) National Institute of General Medical Sciences grant 5K12GM068524; NIH National Cancer Institute (NCI) grant 2P30CA023100-28; NIH NCI grants R01CA205944, R21CA189705 and R21CA194679; the Leukemia & Lymphoma Society (0754-14); the Sanford Stem Cell Clinical Center; the San Diego Foundation; the Ratner Family Foundation; and the Swedish Childhood Cancer Foundation (Barncancerfonden).

Author information

Authors and Affiliations

  1. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, 92093, California, USA

    Qingfei Jiang, Leslie A. Crews, Frida Holm & Catriona H. M. Jamieson

Authors
  1. Qingfei Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leslie A. Crews
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frida Holm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Catriona H. M. Jamieson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catriona H. M. Jamieson.

Ethics declarations

Competing interests

C.H.M.J. receives research funding by sponsored research agreement with GlaxoSmithKline (GSK DPAc001) and a laboratory service agreement with Johnson & Johnson (#15-0230). The other authors declare no competing interests.

Related links

FURTHER INFORMATION

DARNED

RADAR

PowerPoint slides

Glossary

5′-Untranslated regions

(UTRs). Located upstream of the translation initiation codon, the 5′-UTRs are important for translational regulation of mRNA transcripts.

3′-UTRs

(Untranslated regions). The 3′-UTRs have an important role in regulation of gene expression by controlling RNA degradation, cellular localization and translation.

Alu elements

A class of SINE elements, Alu elements comprise approximately 10% of the human genome. Inverted Alu elements are favourable targets of adenosine deaminase acting on double-stranded RNA (ADAR)-mediated RNA editing; as much as 90% of adenosine-to-inosine editing in the human transcriptome occurs within Alu elements.

Short interspersed nuclear element

(SINE). Presented at high frequency in the eukaryotic genome, SINEs are short (<700 bp) non-coding DNA sequences that retrotranspose themselves by a copy and paste mechanism.

Long interspersed nuclear elements

(LINEs). Similar to SINEs, LINEs are a class of retrotransposons (∼6kb) comprising approximately 17% of the human genome. They consist of a 5′-untranslated region (UTR), two open reading frames (ORF1 and ORF2) and a 3′-UTR. Misregulation of LINEs has been linked to tumorigenesis by retrotransposition-dependent and -independent functions.

Primary microRNAs

(Pri-miRNAs). The miRNA genes are transcribed by RNA polymerase II and cleaved to large pri-miRNA transcripts that are subsequently cleaved by DROSHA to form the precursor miRNA (pre-miRNA) transcripts.

Precursor microRNAs

(Pre-miRNAs). Pre-miRNA transcripts are exported from the nucleus by exportin 5 (XPO5), to be processed by DICER1 to form the mature miRNAs.

Blast crisis (BC) CML

BC CML is characterized by the elevated numbers of self-renewing cancer stem cells residing in the granulocyte–macrophage progenitor compartment, which express higher levels of the BCR–ABL1 oncogene and nuclear β-catenin. Patients with BC live an average of 3–6 months.

Crosslinking immunoprecipitation

(CLIP). CLIP is UV crosslinking followed by immunoprecipitation to examine the interactions between RNA transcripts and RNA binding proteins and location of RNA modifications. The isolated RNA is reverse transcribed for PCR, microarray or sequencing analysis.

LIN−SCA1+KIT+ cells

These cells are lineage-negative (LIN−), stem-cell antigen 1 positive (SCA1+) and KIT positive (KIT+) and make up a population of mouse bone marrow cells (∼0.5%) with long-term multi-lineage repopulation capacity.

Accelerated phase CML

(AP CML). In this phase of chronic myeloid leukaemia (CML), the cancer stem cells often acquire new genetic mutations, causing more severe symptoms and poor response to treatment.

Chronic phase CML

(CP CML). The beginning phase of chronic myeloid leukaemia (CML) in which the patients have acquired the BCR–ABL1 oncogene, which induces abnormal production of myeloid cells. The standard treatment for CP CML is tyrosine kinase inhibitors such as imatinib or dasatinib. However, CP CML can progress slowly to an accelerated phase and later a blastic phase (blast crisis) over several years.

Branch site

Also called branch point; these occur predominantly at adenosine, highly conserved and closely localized to the 3′-splice site of an intron. The consensus sequence for an intron branch site (in IUPAC nucleic acid notation) is Y-U-R-A-C (20–50 nucleotides upstream of the acceptor site). Intronic RNA editing events, point mutations in the underlying DNA or errors during transcription have the potential to either destroy a branch site or activate a cryptic splice site in part of the transcript that is usually not spliced.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, Q., Crews, L., Holm, F. et al. RNA editing-dependent epitranscriptome diversity in cancer stem cells. Nat Rev Cancer 17, 381–392 (2017). https://doi.org/10.1038/nrc.2017.23

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2017.23

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