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The emerging role of lncRNAs in cancer

Abstract

It is increasingly evident that many of the genomic mutations in cancer reside inside regions that do not encode proteins. However, these regions are often transcribed into long noncoding RNAs (lncRNAs). The recent application of next-generation sequencing to a growing number of cancer transcriptomes has indeed revealed thousands of lncRNAs whose aberrant expression is associated with different cancer types. Among the few that have been functionally characterized, several have been linked to malignant transformation. Notably, these lncRNAs have key roles in gene regulation and thus affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. This review aims to summarize current knowledge of lncRNAs from the cancer perspective. It discusses the strategies that led to the identification of cancer-related lncRNAs and the methodologies and challenges involving the study of these molecules, as well as the imminent applications of these findings to the clinic.

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Figure 1: Identification and characterization of lncRNAs with roles in cancer.
Figure 2: LncRNAs are part of the c-MYC oncogenic and p53 tumor suppressor networks.
Figure 3: Diverse mechanisms of cancer-related lncRNAs.

References

  1. Maurano, M.T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Huarte, M. et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409–419 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zheng, G.X., Do, B.T., Webster, D.E., Khavari, P.A. & Chang, H.Y. Dicer-microRNA-Myc circuit promotes transcription of hundreds of long noncoding RNAs. Nat. Struct. Mol. Biol. 21, 585–590 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yu, W. et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451, 202–206 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yap, K.L. et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol. Cell 38, 662–674 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kotake, Y. et al. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene 30, 1956–1962 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Cunnington, M.S., Santibanez Koref, M., Mayosi, B.M., Burn, J. & Keavney, B. Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet. 6, e1000899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang, E.B. et al. Long noncoding RNA ANRIL indicates a poor prognosis of gastric cancer and promotes tumor growth by epigenetically silencing of miR-99a/miR-449a. Oncotarget 5, 2276–2292 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. Esteller, M. Non-coding RNAs in human disease. Nat. Rev. Genet. 12, 861–874 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Sanchez, Y. & Huarte, M. Long non-coding RNAs: challenges for diagnosis and therapies. Nucleic Acid Ther. 23, 15–20 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ling, H. et al. Junk DNA and the long non-coding RNA twist in cancer genetics. Oncogene 34, 5003–5011 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bussemakers, M.J. et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 59, 5975–5979 (1999).

    CAS  PubMed  Google Scholar 

  16. Srikantan, V. et al. PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc. Natl. Acad. Sci. USA 97, 12216–12221 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hessels, D. et al. DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur. Urol. 44, 8–15 discussion, 15–16 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Yang, L. et al. lncRNA-dependent mechanisms of androgen-receptor–regulated gene activation programs. Nature 500, 598–602 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hung, C.L. et al. A long noncoding RNA connects c-Myc to tumor metabolism. Proc. Natl. Acad. Sci. USA 111, 18697–18702 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ji, P. et al. MALAT-1, a novel noncoding RNA, and thymosin β-4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22, 8031–8041 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Gutschner, T., Hammerle, M. & Diederichs, S. MALAT1–a paradigm for long noncoding RNA function in cancer. J. Mol. Med. 91, 791–801 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Tripathi, V. et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol. Cell 39, 925–938 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang, L. et al. ncRNA- and Pc2 methylation–dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147, 773–788 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. West, J.A. et al. The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites. Mol. Cell 55, 791–802 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Engreitz, J.M. et al. RNA-RNA interactions enable specific targeting of noncoding RNAs to nascent pre-mRNAs and chromatin sites. Cell 159, 188–199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Iyer, M.K. et al. The landscape of long noncoding RNAs in the human transcriptome. Nat. Genet. 47, 199–208 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hu, X. et al. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell 26, 344–357 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Puente, X.S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature doi:10.1038/nature14666 (22 July 2015).

  31. Freedman, M.L. et al. Principles for the post-GWAS functional characterization of cancer risk loci. Nat. Genet. 43, 513–518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pandey, G.K. et al. The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. Cancer Cell 26, 722–737 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Verhaegh, G.W. et al. Polymorphisms in the H19 gene and the risk of bladder cancer. Eur. Urol. 54, 1118–1126 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Matouk, I.J. et al. The H19 non-coding RNA is essential for human tumor growth. PLoS ONE 2, e845 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Angrand, P.O., Vennin, C., Le Bourhis, X. & Adriaenssens, E. The role of long non-coding RNAs in genome formatting and expression. Front. Genet. 6, 165 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang, C. et al. Tag SNPs in long non-coding RNA H19 contribute to susceptibility to gastric cancer in the Chinese Han population. Oncotarget 6, 15311–15320 (2015).

    PubMed  PubMed Central  Google Scholar 

  37. Perez-Llamas, C. & Lopez-Bigas, N. Gitools: analysis and visualisation of genomic data using interactive heat-maps. PLoS ONE 6, e19541 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Marín-Béjar, O. et al. Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2. Genome Biol. 14, R104 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huarte, M. & Rinn, J.L. Large non-coding RNAs: missing links in cancer? Hum. Mol. Genet. 19, R152–R161 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sánchez, Y. et al. Genome-wide analysis of the human p53 transcriptional network unveils a lncRNA tumour suppressor signature. Nat. Commun. 5, 5812 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Hung, T. et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat. Genet. 43, 621–629 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Feldstein, O. et al. The long non-coding RNA ERIC is regulated by E2F and modulates the cellular response to DNA damage. Mol. Cancer 12, 131 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hart, J.R., Roberts, T.C., Weinberg, M.S., Morris, K.V. & Vogt, P.K. MYC regulates the non-coding transcriptome. Oncotarget 5, 12543–12554 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kim, T. et al. Role of MYC-regulated long noncoding RNAs in cell cycle regulation and tumorigenesis. J. Natl. Cancer Inst. 107, dju505 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Louro, R. et al. Androgen responsive intronic non-coding RNAs. BMC Biol. 5, 4 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang, L.G. et al. Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex. Cancer Res. 68, 2678–2688 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Takayama, K. et al. Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J. 32, 1665–1680 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chakravarty, D. et al. The oestrogen receptor α-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat. Commun. 5, 5383 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Guttman, M. et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477, 295–300 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bennett, C.F. & Swayze, E.E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50, 259–293 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Kole, R., Krainer, A.R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat. Rev. Drug Discov. 11, 125–140 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Miller, J.C. et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nat. Biotechnol. 25, 778–785 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Zhang, F. et al. Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription. Nat. Biotechnol. 29, 149–153 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wiedenheft, B., Sternberg, S.H. & Doudna, J.A. RNA-guided genetic silencing systems in bacteria and archaea. Nature 482, 331–338 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Ho, T.T. et al. Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. Nucleic Acids Res. 43, e17 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Han, J. et al. Efficient in vivo deletion of a large imprinted lncRNA by CRISPR/Cas9. RNA Biol. 11, 829–835 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Eißmann, M. et al. Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development. RNA Biol. 9, 1076–1087 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Xiang, J.F. et al. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 24, 513–531 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Konermann, S. et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517, 583–588 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Gutschner, T. & Diederichs, S. The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol. 9, 703–719 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yang, G., Lu, X. & Yuan, L. LncRNA: a link between RNA and cancer. Biochim. Biophys. Acta 1839, 1097–1109 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Keniry, A. et al. The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat. Cell Biol. 14, 659–665 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang, F. et al. Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol. Cell 49, 1083–1096 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Li, L. & Chang, H.Y. Physiological roles of long noncoding RNAs: insight from knockout mice. Trends Cell Biol. 24, 594–602 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sauvageau, M. et al. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2, e01749 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Grote, P. et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev. Cell 24, 206–214 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yildirim, E. et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152, 727–742 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Necsulea, A. et al. The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature 505, 635–640 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Derrien, T. et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 22, 1775–1789 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ulitsky, I., Shkumatava, A., Jan, C.H., Sive, H. & Bartel, D.P. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147, 1537–1550 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ulitsky, I. & Bartel, D.P. lincRNAs: genomics, evolution, and mechanisms. Cell 154, 26–46 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bejerano, G. et al. Ultraconserved elements in the human genome. Science 304, 1321–1325 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Calin, G.A. et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 12, 215–229 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Schorderet, P. & Duboule, D. Structural and functional differences in the long non-coding RNA hotair in mouse and human. PLoS Genet. 7, e1002071 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rinn, J.L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li, L. et al. Targeted disruption of Hotair leads to homeotic transformation and gene derepression. Cell Rep. 5, 3–12 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, B. et al. The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Rep. 2, 111–123 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nakagawa, S., Naganuma, T., Shioi, G. & Hirose, T. Paraspeckles are subpopulation-specific nuclear bodies that are not essential in mice. J. Cell Biol. 193, 31–39 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nakagawa, S. et al. The lncRNA Neat1 is required for corpus luteum formation and the establishment of pregnancy in a subpopulation of mice. Development 141, 4618–4627 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Trimarchi, T. et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 158, 593–606 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Léveillé, N. et al. Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA. Nat. Commun. 6, 6520 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Zhou, Y. et al. Activation of p53 by MEG3 non-coding RNA. J. Biol. Chem. 282, 24731–24742 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Winkle, M. et al. Long noncoding RNAs as a novel component of the Myc transcriptional network. FASEB J. 29, 2338–2346 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Jia, L. et al. Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet. 5, e1000597 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sur, I., Tuupanen, S., Whitington, T., Aaltonen, L.A. & Taipale, J. Lessons from functional analysis of genome-wide association studies. Cancer Res. 73, 4180–4184 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Ling, H. et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 23, 1446–1461 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kim, T. et al. Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5. Proc. Natl. Acad. Sci. USA 111, 4173–4178 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tseng, Y.Y. et al. PVT1 dependence in cancer with MYC copy-number increase. Nature 512, 82–86 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Prensner, J.R. et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat. Biotechnol. 29, 742–749 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Prensner, J.R. et al. PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Res. 74, 1651–1660 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Prensner, J.R. et al. The long non-coding RNA PCAT-1 promotes prostate cancer cell proliferation through cMyc. Neoplasia 16, 900–908 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Prensner, J.R. et al. The IncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer. Oncotarget 5, 1434–1438 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Dawson, M.A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Marchese, F.P. & Huarte, M. Long non-coding RNAs and chromatin modifiers: Their place in the epigenetic code. Epigenetics 9, 21–26 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Guttman, M. & Rinn, J.L. Modular regulatory principles of large non-coding RNAs. Nature 482, 339–346 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Khalil, A.M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 106, 11667–11672 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Zhang, J., Zhang, P., Wang, L., Piao, H.L. & Ma, L. Long non-coding RNA HOTAIR in carcinogenesis and metastasis. Acta Biochim. Biophys. Sin. (Shanghai) 46, 1–5 (2014).

    Article  CAS  Google Scholar 

  98. Tsai, M.C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhang, E.B. et al. P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression. Cell Death Dis. 5, e1243 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Davidovich, C., Zheng, L., Goodrich, K.J. & Cech, T.R. Promiscuous RNA binding by Polycomb repressive complex 2. Nat. Struct. Mol. Biol. 20, 1250–1257 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Prensner, J.R. et al. The long noncoding RNA SCHLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat. Genet. 45, 1392–1398 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mourtada-Maarabouni, M., Pickard, M.R., Hedge, V.L., Farzaneh, F. & Williams, G.T. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 28, 195–208 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Kino, T., Hurt, D.E., Ichijo, T., Nader, N. & Chrousos, G.P. Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci. Signal. 3, ra8 (2010).

    PubMed  PubMed Central  Google Scholar 

  104. Lee, J.T. & Bartolomei, M.S. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152, 1308–1323 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Yoon, J.H. et al. LincRNA-p21 suppresses target mRNA translation. Mol. Cell 47, 648–655 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Godinho, M., Meijer, D., Setyono-Han, B., Dorssers, L.C. & van Agthoven, T. Characterization of BCAR4, a novel oncogene causing endocrine resistance in human breast cancer cells. J. Cell. Physiol. 226, 1741–1749 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Xing, Z. et al. lncRNA directs cooperative epigenetic regulation downstream of chemokine signals. Cell 159, 1110–1125 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Beltran, M. et al. A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev. 22, 756–769 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Salmena, L., Poliseno, L., Tay, Y., Kats, L. & Pandolfi, P.P. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Poliseno, L. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033–1038 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Hansen, T.B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).

    Article  CAS  PubMed  Google Scholar 

  114. Poliseno, L. et al. Deletion of PTENP1 pseudogene in human melanoma. J. Invest. Dermatol. 131, 2497–2500 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cabili, M.N. et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Panzitt, K. et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 132, 330–342 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Record, M., Subra, C., Silvente-Poirot, S. & Poirot, M. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem. Pharmacol. 81, 1171–1182 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Donner, A. A platform for RNA. SciBX 6 doi:10.1038/scibx.2013.1151 (24 October 2013).

  119. Meng, L. et al. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 518, 409–412 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Ling, H., Fabbri, M. & Calin, G.A. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat. Rev. Drug Discov. 12, 847–865 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mizrahi, A. et al. Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences. J. Transl. Med. 7, 69 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Jiang, J. et al. Translating dosage compensation to trisomy 21. Nature 500, 296–300 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chu, C., Qu, K., Zhong, F.L., Artandi, S.E. & Chang, H.Y. Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol. Cell 44, 667–678 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Simon, M.D. et al. The genomic binding sites of a noncoding RNA. Proc. Natl. Acad. Sci. USA 108, 20497–20502 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Engreitz, J.M. et al. The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341, 1237973 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. McHugh, C.A., Russell, P. & Guttman, M. Methods for comprehensive experimental identification of RNA-protein interactions. Genome Biol. 15, 203 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hezroni, H. et al. Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species. Cell Rep. 11, 1110–1122 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zhou, Y., Zhang, X. & Klibanski, A. MEG3 noncoding RNA: a tumor suppressor. J. Mol. Endocrinol. 48, R45–R53 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Wilusz, J.E., Freier, S.M. & Spector, D.L. 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135, 919–932 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank the members of my laboratory and D. O'Brien for critical reading of the manuscript, and I apologize to colleagues whose work was not discussed or cited owing to space constraints. I am supported by European Research Council grant ERC-2011-StG 281877, and by Spanish Ministry of Science Grant RYC-2011-08347.

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Correspondence to Maite Huarte.

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Huarte, M. The emerging role of lncRNAs in cancer. Nat Med 21, 1253–1261 (2015). https://doi.org/10.1038/nm.3981

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