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Understanding the Role of Long Noncoding RNAs in the Cancer Genome

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Abstract

The secrets of long noncoding RNAs, like other noncoding RNAs that are often referred to as the “dark matter” of the genome, are gradually coming to light. Knowledge from the Encyclopedia of DNA Elements project revealed that greater than 70 % of the genome is actively transcribed and thousands of long noncoding RNA (lncRNA) transcripts, which are greater than 200 base pairs without protein-coding potential, have been annotated. Increasing evidence shows that lncRNAs play crucial roles in development, stem cell pluripotency, differentiation, cell-cycle control, and diseases including cancer. The molecular actions of lncRNAs are involved in regulation of gene expression, interaction with chromatin-modifying complexes, and DNA–RNA–protein hybrid. In this chapter, we introduce the biogenesis of lncRNAs, their functionality and mechanisms of action, and strategies for discovery of lncRNAs and highlight the functional role of lncRNAs in cancer development. We briefly discuss our own work with lncRNAs. Our aim is to pinpoint the complex and diverse functions of these enigmatic molecules in cancer biology and expand our understanding of the cancer initiatome.

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References

  1. Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74. Epub 2012/09/08.

    Article  PubMed  CAS  Google Scholar 

  2. Wu W, Sun M, Zou GM, Chen J. MicroRNA and cancer: current status and prospective. Int J Cancer. 2007;120(5):953–60. Epub 2006/12/14.

    Article  PubMed  CAS  Google Scholar 

  3. Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, et al. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature. 2002;420(6915):563–73. Epub 2002/12/06.

    Article  PubMed  Google Scholar 

  4. Brannan CI, Dees EC, Ingram RS, Tilghman SM. The product of the H19 gene may function as an RNA. Mol Cell Biol. 1990;10(1):28–36. Epub 1990/01/01.

    PubMed  CAS  Google Scholar 

  5. Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature. 1991;349(6304):38–44. Epub 1991/01/03.

    Article  PubMed  CAS  Google Scholar 

  6. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22(9):1775–89. Epub 2012/09/08.

    Article  PubMed  CAS  Google Scholar 

  7. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458(7235):223–7. Epub 2009/02/03.

    Article  PubMed  CAS  Google Scholar 

  8. Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell. 2007;12(3):215–29. Epub 2007/09/06.

    Article  PubMed  CAS  Google Scholar 

  9. Chen LL, Carmichael GG. Long noncoding RNAs in mammalian cells: what, where, and why? Wiley Interdiscip Rev RNA. 2010;1(1):2–21. Epub 2010/07/01.

    Article  PubMed  CAS  Google Scholar 

  10. Lipovich L, Johnson R, Lin CY. MacroRNA underdogs in a microRNA world: evolutionary, regulatory, and biomedical significance of mammalian long non-protein-coding RNA. Biochim Biophys Acta. 2010;1799(9):597–615. Epub 2010/10/19.

    Article  PubMed  CAS  Google Scholar 

  11. Cheng J, Kapranov P, Drenkow J, Dike S, Brubaker S, Patel S, et al. Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science. 2005;308(5725):1149–54. Epub 2005/03/26.

    Article  PubMed  CAS  Google Scholar 

  12. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011;25(18):1915–27. Epub 2011/09/06.

    Article  PubMed  CAS  Google Scholar 

  13. Novikova IV, Hennelly SP, Sanbonmatsu KY. Sizing up long non-coding RNAs: do lncRNAs have secondary and tertiary structure? Bioarchitecture. 2012;2(6):189–99. Epub 2012/12/06.

    Google Scholar 

  14. Gibb EA, Vucic EA, Enfield KS, Stewart GL, Lonergan KM, Kennett JY, et al. Human cancer long non-coding RNA transcriptomes. PLoS One. 2011;6(10):e25915. Epub 2011/10/13.

    Article  PubMed  CAS  Google Scholar 

  15. Ellis BC, Molloy PL, Graham LD. CRNDE: a long non-coding RNA involved in CanceR, Neurobiology, and DEvelopment. Front Genet. 2012;3:270. Epub 2012/12/12.

    Article  PubMed  CAS  Google Scholar 

  16. Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science. 2007;316(5830):1484–8. Epub 2007/05/19.

    Article  PubMed  CAS  Google Scholar 

  17. Clark MB, Johnston RL, Inostroza-Ponta M, Fox AH, Fortini E, Moscato P, et al. Genome-wide analysis of long noncoding RNA stability. Genome Res. 2012;22(5):885–98. Epub 2012/03/13.

    Article  PubMed  CAS  Google Scholar 

  18. Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66. Epub 2012/06/06.

    Article  PubMed  CAS  Google Scholar 

  19. Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS, et al. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci. 2010;11:14. Epub 2010/02/09.

    Article  PubMed  Google Scholar 

  20. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell. 2010;39(6):925–38. Epub 2010/08/28.

    Article  PubMed  CAS  Google Scholar 

  21. Kretz M, Webster DE, Flockhart RJ, Lee CS, Zehnder A, Lopez-Pajares V, et al. Suppression of progenitor differentiation requires the long noncoding RNA ANCR. Genes Dev. 2012;26(4):338–43. Epub 2012/02/04.

    Article  PubMed  CAS  Google Scholar 

  22. Kretz M, Siprashvili Z, Chu C, Webster DE, Zehnder A, Qu K, et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature. 2013;493:231–5. Epub 2012/12/04.

    Article  PubMed  CAS  Google Scholar 

  23. Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet. 2010;42(12):1113–7. Epub 2010/11/09.

    Article  PubMed  CAS  Google Scholar 

  24. Wapinski O, Chang HY. Long noncoding RNAs and human disease. Trends Cell Biol. 2011;21(6):354–61. Epub 2011/05/10.

    Article  PubMed  CAS  Google Scholar 

  25. Lee JT. Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome. Genes Dev. 2009;23(16):1831–42. Epub 2009/08/18.

    Article  PubMed  CAS  Google Scholar 

  26. Lee MP, DeBaun MR, Mitsuya K, Galonek HL, Brandenburg S, Oshimura M, et al. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc Natl Acad Sci U S A. 1999;96(9):5203–8. Epub 1999/04/29.

    Article  PubMed  CAS  Google Scholar 

  27. Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science. 2008;322(5902):750–6. Epub 2008/11/01.

    Article  PubMed  CAS  Google Scholar 

  28. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329(5992):689–93. Epub 2010/07/10.

    Article  PubMed  CAS  Google Scholar 

  29. Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009;106(28):11667–72. Epub 2009/07/03.

    Article  PubMed  CAS  Google Scholar 

  30. Zhao J, Ohsumi TK, Kung JT, Ogawa Y, Grau DJ, Sarma K, et al. Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol Cell. 2010;40(6):939–53. Epub 2010/12/22.

    Article  PubMed  CAS  Google Scholar 

  31. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007;129(7):1311–23. Epub 2007/07/03.

    Article  PubMed  CAS  Google Scholar 

  32. Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature. 2011;470(7333):284–8. Epub 2011/02/11.

    Article  PubMed  CAS  Google Scholar 

  33. Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465(7301):1033–8. Epub 2010/06/26.

    Article  PubMed  CAS  Google Scholar 

  34. Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale JL, De S, et al. LincRNA-p21 suppresses target mRNA translation. Mol Cell. 2012;47(4):648–55. Epub 2012/07/31.

    Article  PubMed  CAS  Google Scholar 

  35. Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22(39):8031–41. Epub 2003/09/13.

    Article  PubMed  Google Scholar 

  36. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834–8.

    Article  PubMed  CAS  Google Scholar 

  37. O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435(7043):839–43.

    Article  PubMed  Google Scholar 

  38. Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011;71(20):6320–6. Epub 2011/08/25.

    Article  PubMed  CAS  Google Scholar 

  39. Ng SY, Johnson R, Stanton LW. Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J. 2012;31(3):522–33. Epub 2011/12/24.

    Article  PubMed  CAS  Google Scholar 

  40. Kapranov P, Cawley SE, Drenkow J, Bekiranov S, Strausberg RL, Fodor SP, et al. Large-scale transcriptional activity in chromosomes 21 and 22. Science. 2002;296(5569):916–9. Epub 2002/05/04.

    Article  PubMed  CAS  Google Scholar 

  41. Rinn JL, Euskirchen G, Bertone P, Martone R, Luscombe NM, Hartman S, et al. The transcriptional activity of human Chromosome 22. Genes Dev. 2003;17(4):529–40. Epub 2003/02/26.

    Article  PubMed  CAS  Google Scholar 

  42. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6. Epub 2010/04/16.

    Article  PubMed  CAS  Google Scholar 

  43. Brunner AL, Beck AH, Edris B, Sweeney RT, Zhu SX, Li R, et al. Transcriptional profiling of lncRNAs and novel transcribed regions across a diverse panel of archived human cancers. Genome Biol. 2012;13(8):R75. Epub 2012/08/30.

    Article  PubMed  Google Scholar 

  44. Li D, Feng J, Wu T, Wang Y, Sun Y, Ren J, et al. Long intergenic noncoding RNA HOTAIR is overexpressed and regulates PTEN methylation in laryngeal squamous cell carcinoma. Am J Pathol. 2013;182:64–70. Epub 2012/11/13.

    Article  PubMed  CAS  Google Scholar 

  45. Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, et al. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013;32:1616–25. Epub 2012/05/23.

    Article  PubMed  CAS  Google Scholar 

  46. Tsai MC, Spitale RC, Chang HY. Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res. 2011;71(1):3–7. Epub 2011/01/05.

    Article  PubMed  CAS  Google Scholar 

  47. Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010;142(3):409–19. Epub 2010/08/03.

    Article  PubMed  CAS  Google Scholar 

  48. Niinuma T, Suzuki H, Nojima M, Nosho K, Yamamoto H, Takamaru H, et al. Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Cancer Res. 2012;72(5):1126–36. Epub 2012/01/20.

    Article  PubMed  CAS  Google Scholar 

  49. Han Y, Liu Y, Gui Y, Cai Z. Long intergenic non-coding RNA TUG1 is overexpressed in urothelial carcinoma of the bladder. J Surg Oncol. 2013;107:555–9. Epub 2012/09/11.

    Article  PubMed  CAS  Google Scholar 

  50. Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol. 2011;29(8):742–9. Epub 2011/08/02.

    Article  PubMed  CAS  Google Scholar 

  51. Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, 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. 2010;38(5):662–74. Epub 2010/06/15.

    Article  PubMed  CAS  Google Scholar 

  52. Zhou Y, Zhang X, Klibanski A. MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol. 2012;48(3):R45–53. Epub 2012/03/07.

    Article  PubMed  CAS  Google Scholar 

  53. Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, et al. Activation of p53 by MEG3 non-coding RNA. J Biol Chem. 2007;282(34):24731–42. Epub 2007/06/16.

    Article  PubMed  CAS  Google Scholar 

  54. Benetatos L, Hatzimichael E, Dasoula A, Dranitsaris G, Tsiara S, Syrrou M, et al. CpG methylation analysis of the MEG3 and SNRPN imprinted genes in acute myeloid leukemia and myelodysplastic syndromes. Leuk Res. 2010;34(2):148–53. Epub 2009/07/15.

    Article  PubMed  CAS  Google Scholar 

  55. Beck-Engeser GB, Lum AM, Huppi K, Caplen NJ, Wang BB, Wabl M. Pvt1-encoded microRNAs in oncogenesis. Retrovirology. 2008;5:4. Epub 2008/01/16.

    Article  PubMed  Google Scholar 

  56. Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012;488(7409):49–56. Epub 2012/07/27.

    Article  PubMed  CAS  Google Scholar 

  57. Barsotti AM, Beckerman R, Laptenko O, Huppi K, Caplen NJ, Prives C. p53-Dependent induction of PVT1 and miR-1204. J Biol Chem. 2012;287(4):2509–19. Epub 2011/11/24.

    Article  PubMed  CAS  Google Scholar 

  58. Ozgur E, Mert U, Isin M, Okutan M, Dalay N, Gezer U. Differential expression of long non-coding RNAs during genotoxic stress-induced apoptosis in HeLa and MCF-7 cells. Clin Exp Med. 2012;13(2):119–26. Epub 2012/04/11.

    Google Scholar 

  59. Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009;28(2):195–208. Epub 2008/10/07.

    Article  PubMed  CAS  Google Scholar 

  60. Chung S, Nakagawa H, Uemura M, Piao L, Ashikawa K, Hosono N, et al. Association of a novel long non-coding RNA in 8q24 with prostate cancer susceptibility. Cancer Sci. 2011;102(1):245–52. Epub 2010/09/30.

    Article  PubMed  CAS  Google Scholar 

  61. Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73:1180–9. Epub 2012/12/18.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

J.A.C. is an Alberta Innovates Health Solutions (AIHS) Clinical Investigator. J.A.C. and W.W. are supported by funds from the Kids Cancer Care Foundation of Alberta, Genome Canada, the Clark H. Smith Brain Tumor Centre, and the Ross Family Fund and Family of Kathleen Lorette. We are grateful to Dr. Fred Biddle for the stimulating discussion about cancer initiatome and for critical reading of the manuscript.

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Correspondence to Wei Wu or Jennifer A. Chan .

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Wu, W., Chan, J.A. (2013). Understanding the Role of Long Noncoding RNAs in the Cancer Genome. In: Wu, W., Choudhry, H. (eds) Next Generation Sequencing in Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7645-0_10

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