REVIEW

Long noncoding RNAs are a promising therapeutic target in various diseases

About authors

1 Laboratory of Functional Genomics,
Research Centre of Medical Genetics, Moscow, Russia

2 Laboratory of Medical Genetic Technologies, Department of Basic Research of MDRI,
Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia

3 Genomic Functional Analysis Laboratory,
Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia

Correspondence should be addressed: Alexandra Filatova
ul. Moskvorechie, d. 1, Moscow, Russia, 115478; ur.xednay@ccaam

About paper

Contribution of the authors to this work: Filatova AYu — planning, literature analysis, drafting of a manuscript; Sparber PA — literature analysis, drafting of a manuscript; Krivosheeva IA — literature analysis, drafting of a manuscript; Skoblov MYu — drafting of a manuscript. All authors participated in editing of the manuscript.

Received: 2017-06-25 Accepted: 2017-06-28 Published online: 2017-07-18
|
  1. Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski E et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 2012 Sep; 22 (9): 1760–74. DOI: 10.1101/gr.135350.111.
  2. Kornienko AE, Dotter CP, Guenzl PM, Gisslinger H, Gisslinger B, Cleary C et al. Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans. Genome Biol. 2016 Jan 29; 17: 14. DOI: 10.1186/s13059-016-0873-8.
  3. Leucci E, Vendramin R, Spinazzi M, Laurette P, Fiers M, Wouters J et al. Melanoma addiction to the long non-coding RNA SAMMSON. Nature. 2016 Mar 24; 531 (7595): 518–22. DOI: 10.1038/nature17161.
  4. 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 Oct 31; 322 (5902): 750–6. DOI: 10.1126/science.1163045.
  5. Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD et al. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell. 2011 Nov 11; 147 (4): 773–88.
  6. Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell. 2008 Oct 24; 32 (2): 232–46. DOI: 10.1016/j.molcel.2008.08.022.
  7. 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 Jun 29; 129 (7): 1311–23. DOI: 10.1016/j.cell.2007.05.022.
  8. 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 Aug 6; 329 (5992): 689–93. DOI: 10.1126/science.1192002.
  9. Cabianca DS, Casa V, Bodega B, Xynos A, Ginelli E, Tanaka Y et al. A long ncRNA links copy number variation to a polycomb/ trithorax epigenetic switch in FSHD muscular dystrophy. Cell. 2012 May 11; 149 (4): 819–31. DOI: 10.1016/j.cell.2012.03.035.
  10. Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011 Oct 14; 147 (2): 358–69. DOI: 10.1016/j.cell.2011.09.028.
  11. Karreth FA, Tay Y, Perna D, Ala U, Tan SM, Rust AG et al. In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell. 2011 Oct 14; 147 (2): 382–95. DOI: 10.1016/j.cell.2011.09.032.
  12. Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale JL, De S et al. LincRNA-p21 suppresses target mRNA translation. Mol Cell. 2012 Aug 24; 47 (4): 648–55. DOI: 10.1016/j.molcel.2012.06.027.
  13. Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE et al. Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008 Jul; 14 (7): 723–30. DOI: 10.1038/nm1784.
  14. Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements. Nature. 2011 Feb 10; 470 (7333): 284–8. DOI: 10.1038/nature09701.
  15. Spector DL, Lamond AI. Nuclear speckles. Cold Spring Harb Perspect Biol. 2011 Feb 1; 3 (2). pii: a000646. DOI: 10.1101/cshperspect.a0000646.
  16. 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 Сell. 2010 Sep 24; 39 (6): 925–38. DOI: 10.1016/j.molcel.2010.08.011.
  17. Engreitz JM, Sirokman K, McDonel P, Shishkin AA, Surka C, Russell P et al. RNA-RNA interactions enable specific targeting of noncoding RNAs to nascent Pre-mRNAs and chromatin sites. Cell. 2014 Sep 25; 159 (1): 188–99. DOI: 10.1016/j.cell.2014.08.018.
  18. Chen, Wang Z, WangD, Qui C, Liu M, Chen X et al. LncRNADisease: a database for long-non-coding RNA-associated diseases. Nucleic Acids Res. 2013 Jan 1; 41 (Database issue): D983–6. DOI: 10.1093/nar/gks1099.
  19. Xing Z, Lin A, Li C, Liang K, Wang S, Liu Y et al. lncRNA directs cooperative epigenetic regulation downstream of chemokine signals. Cell. 2014 Nov 20; 159 (5): 1110–25. DOI: 10.1016/j.cell.2014.10.013.
  20. Yoshimoto R, Mayeda A, Yoshida M, Nakagawa S. MALAT1 long non-coding RNA in cancer. Biochim Biophys Acta. 2016 Jan; 1859 (1): 192–9. DOI: 10.1016/j.bbagrm.2015.09.012.
  21. Woo CJ, Maier VK, Davey R, Brennan J, Li G, Brothers J 2nd et al. Gene activation of SMN by selective disruption of lncRNA- mediated recruitment of PRC2 for the treatment of spinal muscular atrophy. Proc Natl Acad Sci U S A. 2017 Feb 21; 114 (8): E1509–18. DOI: 10.1073/pnas.1616521114.
  22. Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature. 2015 Feb 19; 518 (7539): 409–12. DOI: 10.1038/nature13975.
  23. Zernov NV, Marakhonov AV, Vyakhireva JV, Guskova AA, Dadalia EL, Skoblov MY. Clinical and Genetic Characteristics and Diagnostic Features of Landouzy–Dejerine Facioscapulohumeral Muscular Dystrophy. Russian Journal of Genetics. 2017; 53 (6): 640–50.
  24. Sun M, Liu XH, Wang KM, Nie FQ, Kong R, Yang JS et al. Downregulation of BRAF activated non-coding RNA is associated with poor prognosis for non-small cell lung cancer and promotes metastasis by affecting epithelial-mesenchymal transition. Mol Cancer. 2014 Mar 21; 13: 68. DOI: 10.1186/1476-4598-13-68.
  25. Pickard MR, Williams GT. Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: implications for chemotherapy. Breast Cancer Res Treat. 2014 Jun; 145 (2): 359–70. DOI: 10.1007/s10549-014-2974-y.
  26. 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 Jan 15; 28 (2): 195–208. DOI:10.1038/onc.2008.373.
  27. Cao S, Liu W, Li F, Zhao W, Qin C. Decreased expression of lncRNA GAS5 predicts a poor prognosis in cervical cancer. Int J Clin Exp Pathol. 2014; 7 (10): 6776–83.
  28. Chung DW, Rudnicki DD, Yu L, Margolis RL. A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression. Hum Mol Genet. 2011 Sep 1; 20 (17): 3467–77. DOI: 10.1093/hmg/ddr263.
  29. Nayerossadat N, Maedeh T, Ali PA. Viral and nonviral delivery systems for gene delivery. Adv Biomed Res. 2012; 1: 27. DOI: 10.4103/2277-9175.98152.
  30. Zhang F, Zhang L, Zhang C. Long noncoding RNAs and tumorigenesis: genetic associations, molecular mechanisms, and therapeutic strategies. Tumour Biol. 2016 Jan; 37 (1): 163–75. DOI: 10.1007/s13277-015-4445-4.
  31. Crooke ST. Molecular mechanisms of action of antisense drugs. Biochim Biophys Acta. 1999 Dec 10; 1489 (1): 31–44.
  32. Rigo F, Seth PP, Bennett CF. Antisense oligonucleotide-based therapies for diseases caused by pre-mRNA processing defects. Adv Exp Med Biol. 2014; 825: 303–52. DOI: 10.1007/978-1-4939-1221-6_9.
  33. Chery J. RNA therapeutics: RNAi and antisense mechanisms and clinical applications. Postdoc J. 2016 Jul; 4 (7): 35–50.
  34. Klug A. The discovery of zinc fingers and their development for practical applications in gene regulation and genome manipulation. Q Rev Biophys. 2010 Feb; 43 (1): 1–21. DOI: 10.1017/S003358351000089.
  35. Boch J, Bonas U. Xanthomonas AvrBs3 family-type III effectors: discovery and function. Annu Rev Phytopathol. 2010; 48: 419– 36. DOI: 10.1146/annurev-phyto-080508-081936.
  36. Nemudryi AA, Valetdinova KR, Medvedev SP, Zakian SM. TALEN and CRISPR/Cas Genome Editing Systems: Tools of Discovery. Acta Naturae. 2014 Jul; 6 (3): 19–40.
  37. Boettcher M, McManus MT. Choosing the Right Tool for the Job: RNAi, TALEN, or CRISPR. Mol Cell. 2015 May 21; 58 (4): 575–85. DOI: 10.1016/j.molcel.2015.04.028.
  38. Schaefer KA, Wu WH, Colgan DF, Tsang SH, Bassuk AG, Mahajan VB. Unexpected mutations after CRISPR-Cas9 editing in vivo. Nat Methods. 2017 May 30; 14 (6): 547–8. DOI: 10.1038/nmeth.4293.
  39. Iyer V, Shen B, Zhang W, Hodgkins A, Keane T, Huang X, et al. Off- target mutations are rare in Cas9-modified mice. Nat Methods. 2015 Jun; 12 (6): 479. DOI: 10.1038/nmeth.3408.
  40. Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z et al. CRISPR/ Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015 May; 6 (5): 363–72. DOI: 10.1007/s13238-015-0153-5.
  41. Chavez A, Scheiman J, Vora S, Pruitt BW, Tuttle M, E PRI, et al. Highly efficient Cas9-mediated transcriptional programming. Nat Methods. 2015 Apr; 12 (4): 326–8. DOI: 10.1038/nmeth.3312.
  42. Gilbert LA, Larson MH, MorsutL, Liu Z, Brar GA, Torres SE et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell. 2013 Jul 18; 154 (2): 442–51. DOI: 10.1016/j.cell.2013.06.044.
  43. Maeder ML, Linder SJ, Cascio VM, Fu Y, Ho QH, Joung JK. CRISPR RNA-guided activation of endogenous human genes. Nat Methods. 2013 Oct; 10 (10): 977–9. DOI: 10.1038/nmeth.2598.
  44. Perez-Pinera P, Kocak DD, Vockley CM, Adler AF, Kabadi AM, Polstein LR, et al. RNA-guided gene activation by CRISPR-Cas9- based transcription factors. Nat Methods. 2013 Oct; 10 (10): 973–6. DOI: 10.1038/nmeth.2600.
  45. Gilbert LA, Horlbeck MA, Adamson B, Villalta JE, Chen Y, Whitehead EH et al. Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation. Cell. 2014 Oct 23; 159 (3): 647–61. DOI: 10.1016/j.cell.2014.09.029.
  46. Meng L, Person RE, Beaudet AL. Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. Hum Mol Genet. 2012 Jul 1; 21 (13): 3001–12. DOI: 10.1093/hmg/dds130.
  47. Goyal A, Myacheva K, Gross M, Klingenberg M, Duran Arque B, Diederichs S. Challenges of CRISPR/Cas9 applications for long non-coding RNA genes. Nucleic Acids Res. 2017 Feb 17; 45 (3): e12. DOI: 10.1093/nar/gkw883.
  48. Ma L, Chua MS, Andrisani O, So S. Epigenetics in hepatocellular carcinoma: an update and future therapy perspectives. World J Gastroenterol. 2014 Jan 14; 20 (2): 333–45. DOI: 10.3748/wjg.v20.i2.333.
  49. Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov. 2011 Oct; 1 (5): 391–407. DOI: 10.1158/2159-8290.CD-11-0209.
  50. Pedram Fatemi R, Salah-Uddin S, Modarresi F, Khoury N, Wahlestedt C, Faghihi MA. Screening for Small-Molecule Modulators of Long Noncoding RNA-Protein Interactions Using AlphaScreen. J Biomol Screen. 2015 Oct; 20 (9): 1132–41. DOI: 10.1177/1087057115594187.
  51. Fatima R, Akhade VS, Pal D, Rao SM. Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets. Mol Cell Ther. 2015; 3: 5. DOI: 10.1186/s40591-015-0042-6.
  52. Zhou X, Ren Y, Zhang J, Zhang C, Zhang K, Han L et al. HOTAIR is a therapeutic target in glioblastoma. Oncotarget. 2015 Apr 10; 6 (10): 8353–65. DOI: 10.18632/oncotarget.3229.
  53. Rubio-Rodriguez D, De Diego Blanco S, Perez M, Rubio-Terres C. Cost-Effectiveness of Drug Treatments for Advanced Melanoma: A Systematic Literature Review. Pharmacoeconomics. 2017 May 27. DOI: 10.1007/s40273-017-0517-1.
  54. American Cancer Society. Cancer Facts and Figures 2017 [Internet]. Atlanta, Georgia: American Cancer Society; 2017 [cited 2017 Jun]. Available from: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf
  55. Godinho M, Meijer D, Setyono-Han B, Dorssers LC, van Agthoven T. Characterization of BCAR4, a novel oncogene causing endocrine resistance in human breast cancer cells. J Сell Physiol. 2011 Jul; 226 (7): 1741–9. DOI: 10.1002/jcp.22503.
  56. 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 Apr 15; 464 (7291): 1071–6. DOI: 10.1038/nature08975.
  57. Yu X, Li Z. Long non-coding RNA HOTAIR: A novel oncogene (Review). Mol Med Rep. 2015 Oct; 12 (4): 5611–8. DOI: 10.3892/mmr.2015.4161.
  58. 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 Jan; 182 (1): 64–70. DOI: 10.1016/j.ajpath.2012.08.042.
  59. 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 Sep 11; 22 (39): 8031–41. DOI: 10.1038/sj.onc.1206928.
  60. 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 Feb 1; 73 (3): 1180–9. DOI: 10.1158/0008-5472.CAN-12-2850.
  61. Nakagawa S, Ip JY, Shioi G, Tripathi V, Zong X, Hirose T et al. Malat1 is not an essential component of nuclear speckles in mice. RNA. 2012 Aug; 18 (8): 1487–99. DOI: 10.1261/rna.033217.112.
  62. Tano K, Mizuno R, Okada T, Rakwal R, Shibato J, Masuo Y et al. MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS letters. 2010 Nov 19; 584 (22): 4575–80. DOI: 10.1016/j.febslet.2010.10.008.
  63. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci. 1991 Oct; 12 (10): 383–8.
  64. St George-Hyslop P, Haass C. Regulatory RNA goes awry in Alzheimer's disease. Nat Med. 2008 Jul; 14 (7): 711–2. DOI: 10.1038/nm0708-711.
  65. Modarresi F, Faghihi MA, Patel NS, Sahagan BG, Wahlestedt C, Lopez-Toledano MA. Knockdown of BACE1-AS Nonprotein-Coding Transcript Modulates Beta-Amyloid-Related Hippocampal Neurogenesis. Int J Alzheimers Dis. 2011; 2011: 929042. DOI: 10.4621/2011/929042.
  66. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000; 15 (3): 228–37.
  67. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995 Jan 13; 80 (1): 155–65.
  68. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A. 1999 May 25; 96 (11): 6307–11.
  69. Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999 Jul; 8 (7): 1177–83.
  70. Fang P, Li L, Zeng J, Zhou WJ, Wu WQ, Zhong ZY et al. Molecular characterization and copy number of SMN1, SMN2 and NAIP in Chinese patients with spinal muscular atrophy and unrelated healthy controls. BMC musculoskelet Disord. 2015 Feb 7; 16: 11. DOI: 10.1186/s12891-015-0457-x.
  71. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002 Feb; 70 (2): 358–68. DOI: 10.1086/338627.
  72. Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015 Nov; 33 (4): 831–46. DOI: 10.1016/j.ncl.2015.07.004.
  73. Porensky PN, Burghes AH. Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum Gene Ther. 2013 May; 24 (5): 489–98. DOI: 10.1089/hum.2012.225.
  74. Walker FO. Huntington's disease. Lancet. 2007 Jan 20; 369 (9557): 218–28. DOI: 10.1016/S0140-6736(07)60111-1.
  75. Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet. 1993 Aug; 4 (4): 387–92.
  76. Petersen MB, Brondum-Nielsen K, Hansen LK, Wulff K. Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county. Am J Med Genet. 1995 Jun 19; 60 (3): 261–2.
  77. Runte M, Huttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K. The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum Mol Genet. 2001 Nov 1; 10 (23): 2687–700.
  78. Yamasaki K, Joh K, Ohta T, Masuzaki H, Ishimaru T, Mukai T, et al. Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. Hum Mol Genet. 2003 Apr 15; 12 (8): 837–47.
  79. Vyakhireva JV, Zernov NV, Marakhonov AV, Guskova AA, Skoblov MYu. [Current approaches for treatment of muscular dystrophies]. Meditsinskaya genetika. 2016; 15 (10): 3–16. Russian.
  80. Bodega B, Ramirez GD, Grasser F, Cheli S, Brunelli S, Mora M, et al. Remodeling of the chromatin structure of the facioscapulohumeral muscular dystrophy (FSHD) locus and upregulation of FSHD-related gene 1 (FRG1) expression during human myogenic differentiation. BMC biology. 2009 Jul 16; 7: 41. DOI: 10.1186/1741-7007-7-41.
  81. Gabellini D, Green MR, Tupler R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell. 2002 Aug 9; 110 (3): 339–48.
  82. Kowaljow V, Marcowycz A, Ansseau E, Conde CB, Sauvage S, Matteotti C, et al. The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul Disord. 2007 Aug; 17 (8): 611–23. DOI: 10.1016/j.nmd.2007.04.002.
  83. Wallace LM, Garwick-Coppens SE, Tupler R, Harper SQ. RNA interference improves myopathic phenotypes in mice over- expressing FSHD region gene 1 (FRG1). Mol Ther. 2011 Nov; 19 (11): 2048–54. DOI: 10.1038/mt.2011.118.