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MALAT1 — a paradigm for long noncoding RNA function in cancer

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Abstract

The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a bona fide long noncoding RNA (lncRNA). MALAT1, also known as nuclear-enriched transcript 2 (NEAT2), was discovered as a prognostic marker for lung cancer metastasis but also has been linked to several other human tumor entities. Recent work established a critical regulatory function of this lncRNA in lung cancer metastasis and cell migration. Moreover, MALAT1 is an interesting target for antimetastatic therapy in non-small cell lung carcinoma. Two alternative modes of action have been proposed for MALAT1: regulation of gene expression or alternative splicing. Although the exact mechanism of action in different physiological and pathological conditions still needs to be elucidated, MALAT1 acts as a regulator of gene expression. Although MALAT1 is highly evolutionary conserved in mammals and plays an important role in cancer and metastasis, MALAT1 is not essential for development in a knockout mouse model under normal physiological conditions. Hence, one central question for the future is finding the right stressor and the pathological or environmental condition which requires MALAT1 expression in vivo and entailing its strong evolutionary conservation. Here, we summarize the current knowledge about this important lncRNA. We introduce its discovery, biogenesis, and regulation and describe its known functions, mechanisms of action, and interaction partners.

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References

  1. Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E et al (2003) MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22:8031–8041

    Article  PubMed  Google Scholar 

  2. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA et al (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39:925–938

    Article  PubMed  CAS  Google Scholar 

  3. Wilusz JE, Freier SM, Spector DL (2008) 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135:919–932

    Article  PubMed  CAS  Google Scholar 

  4. Hutchinson JN, Ensminger AW, Clemson CM, Lynch CR, Lawrence JB, Chess A (2007) A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 8:39

    Article  PubMed  Google Scholar 

  5. Koshimizu TA, Fujiwara Y, Sakai N, Shibata K, Tsuchiya H (2010) Oxytocin stimulates expression of a noncoding RNA tumor marker in a human neuroblastoma cell line. Life Sci 86:455–460

    Article  PubMed  CAS  Google Scholar 

  6. Sunwoo H, Dinger ME, Wilusz JE, Amaral PP, Mattick JS, Spector DL (2009) MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res 19:347–359

    Article  PubMed  CAS  Google Scholar 

  7. Wilusz JE, Spector DL (2010) An unexpected ending: noncanonical 3′ end processing mechanisms. RNA 16:259–266

    Article  PubMed  CAS  Google Scholar 

  8. Wilusz JE, Jnbaptiste CK, Lu LY, Kuhn CD, Joshua-Tor L, Sharp PA (2012) A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails. Genes Dev 26:2392–2407

    Article  PubMed  CAS  Google Scholar 

  9. Brown JA, Valenstein ML, Yario TA, Tycowski KT, Steitz JA (2012) Formation of triple-helical structures by the 3′-end sequences of MALAT1 and MENbeta noncoding RNAs. Proc Natl Acad Sci U S A 109:19202–19207

    Article  PubMed  CAS  Google Scholar 

  10. Tani H, Nakamura Y, Ijiri K, Akimitsu N (2010) Stability of MALAT-1, a nuclear long non-coding RNA in mammalian cells, varies in various cancer cells. Drug Discov Ther 4:235–239

    PubMed  CAS  Google Scholar 

  11. Friedel CC, Dolken L, Ruzsics Z, Koszinowski UH, Zimmer R (2009) Conserved principles of mammalian transcriptional regulation revealed by RNA half-life. Nucleic Acids Res 37:e115

    Article  PubMed  Google Scholar 

  12. Clark MB, Johnston RL, Inostroza-Ponta M, Fox AH, Fortini E, Moscato P, Dinger ME, Mattick JS (2012) Genome-wide analysis of long noncoding RNA stability. Genome Res 22:885–898

    Article  PubMed  CAS  Google Scholar 

  13. Bernard D, Prasanth KV, Tripathi V, Colasse S, Nakamura T, Xuan Z, Zhang MQ, Sedel F, Jourdren L, Coulpier F et al (2010) A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J 29:3082–3093

    Article  PubMed  CAS  Google Scholar 

  14. Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun E, Wancewicz E, Mazur C et al (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14:459–468

    Article  PubMed  CAS  Google Scholar 

  15. Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13:867–878

    Article  PubMed  CAS  Google Scholar 

  16. Kuo PH, Doudeva LG, Wang YT, Shen CK, Yuan HS (2009) Structural insights into TDP-43 in nucleic-acid binding and domain interactions. Nucleic Acids Res 37:1799–1808

    Article  PubMed  CAS  Google Scholar 

  17. Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, Konig J, Hortobagyi T, Nishimura AL, Zupunski V et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458

    Article  PubMed  CAS  Google Scholar 

  18. Macias S, Plass M, Stajuda A, Michlewski G, Eyras E, Caceres JF (2012) DGCR8 HITS-CLIP reveals novel functions for the Microprocessor. Nat Struct Mol Biol 19:760–766

    Article  PubMed  CAS  Google Scholar 

  19. Weinmann L, Hock J, Ivacevic T, Ohrt T, Mutze J, Schwille P, Kremmer E, Benes V, Urlaub H, Meister G (2009) Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell 136:496–507

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. Schmidt LH, Spieker T, Koschmieder S, Humberg J, Jungen D, Bulk E, Hascher A, Wittmer D, Marra A, Hillejan L et al (2011) The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol 6:1984–1992

    Article  PubMed  Google Scholar 

  22. Tano K, Mizuno R, Okada T, Rakwal R, Shibato J, Masuo Y, Ijiri K, Akimitsu N (2010) MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett 584:4575–4580

    Article  PubMed  CAS  Google Scholar 

  23. Gutschner T, Baas M, Diederichs S (2011) Noncoding RNA gene silencing through genomic integration of RNA destabilizing elements using zinc finger nucleases. Genome Res 21:1944–1954

    Article  PubMed  CAS  Google Scholar 

  24. Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M et al (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73:1180–1189

    Article  PubMed  CAS  Google Scholar 

  25. Eissmann M, Gutschner T, Hammerle M, Gunther S, Caudron-Herger M, Gross M, Schirmacher P, Rippe K, Braun T, Zornig M et al (2012) Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development. RNA Biol 9:1076–1087

    Article  PubMed  CAS  Google Scholar 

  26. Nakagawa S, Ip JY, Shioi G, Tripathi V, Zong X, Hirose T, Prasanth KV (2012) Malat1 is not an essential component of nuclear speckles in mice. RNA 18:1487–1499

    Article  PubMed  CAS  Google Scholar 

  27. Zhang B, Arun G, Mao YS, Lazar Z, Hung G, Bhattacharjee G, Xiao X, Booth CJ, Wu J, Zhang C et al (2012) The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Rep 2:111–123

    Article  PubMed  CAS  Google Scholar 

  28. Luo JH, Ren B, Keryanov S, Tseng GC, Rao UN, Monga SP, Strom S, Demetris AJ, Nalesnik M, Yu YP et al (2006) Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology 44:1012–1024

    Article  PubMed  CAS  Google Scholar 

  29. Lin R, Maeda S, Liu C, Karin M, Edgington TS (2007) A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 26:851–858

    Article  PubMed  CAS  Google Scholar 

  30. Lai MC, Yang Z, Zhou L, Zhu QQ, Xie HY, Zhang F, Wu LM, Chen LM, Zheng SS (2012) Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol 29:1810–1816

    Article  PubMed  CAS  Google Scholar 

  31. Guffanti A, Iacono M, Pelucchi P, Kim N, Solda G, Croft LJ, Taft RJ, Rizzi E, Askarian-Amiri M, Bonnal RJ et al (2009) A transcriptional sketch of a primary human breast cancer by 454 deep sequencing. BMC Genomics 10:163

    Article  PubMed  Google Scholar 

  32. Praz V, Jagannathan V, Bucher P (2004) CleanEx: a database of heterogeneous gene expression data based on a consistent gene nomenclature. Nucleic Acids Res 32:D542–D547

    Article  PubMed  CAS  Google Scholar 

  33. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, Van Tine BA, Hoog J, Goiffon RJ, Goldstein TC et al (2012) Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486:353–360

    PubMed  CAS  Google Scholar 

  34. Guo F, Li Y, Liu Y, Wang J, Li G (2010) Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in CaSki human cervical cancer cells suppresses cell proliferation and invasion. Acta Biochim Biophys Sin (Shanghai) 42:224–229

    Article  CAS  Google Scholar 

  35. Yamada K, Kano J, Tsunoda H, Yoshikawa H, Okubo C, Ishiyama T, Noguchi M (2006) Phenotypic characterization of endometrial stromal sarcoma of the uterus. Cancer Sci 97:106–112

    Article  PubMed  CAS  Google Scholar 

  36. Xu C, Yang M, Tian J, Wang X, Li Z (2011) MALAT-1: a long non-coding RNA and its important 3′ end functional motif in colorectal cancer metastasis. Int J Oncol 39:169–175

    PubMed  Google Scholar 

  37. Han Y, Liu Y, Nie L, Gui Y, Cai Z (2013) Inducing cell proliferation inhibition, apoptosis, and motility reduction by silencing long noncoding ribonucleic acid metastasis-associated lung adenocarcinoma transcript 1 in urothelial carcinoma of the bladder. Urology 81(209):e201–e207

    Google Scholar 

  38. Ying L, Chen Q, Wang Y, Zhou Z, Huang Y, Qiu F (2012) Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition. Mol Biosyst 8:2289–2294

    Article  PubMed  CAS  Google Scholar 

  39. Fellenberg J, Bernd L, Delling G, Witte D, Zahlten-Hinguranage A (2007) Prognostic significance of drug-regulated genes in high-grade osteosarcoma. Mod Pathol 20:1085–1094

    Article  PubMed  CAS  Google Scholar 

  40. Davis IJ, Hsi BL, Arroyo JD, Vargas SO, Yeh YA, Motyckova G, Valencia P, Perez-Atayde AR, Argani P, Ladanyi M et al (2003) Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. Proc Natl Acad Sci U S A 100:6051–6056

    Article  PubMed  CAS  Google Scholar 

  41. Spector DL, Lamond AI (2011) Nuclear speckles. Cold Spring Harb Perspect Biol 3(2):a000646

    Article  PubMed  Google Scholar 

  42. Miyagawa R, Tano K, Mizuno R, Nakamura Y, Ijiri K, Rakwal R, Shibato J, Masuo Y, Mayeda A, Hirose T et al (2012) Identification of cis- and trans-acting factors involved in the localization of MALAT-1 noncoding RNA to nuclear speckles. RNA 18:738–751

    Article  PubMed  CAS  Google Scholar 

  43. Clemson CM, Hutchinson JN, Sara SA, Ensminger AW, Fox AH, Chess A, Lawrence JB (2009) An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol Cell 33:717–726

    Article  PubMed  CAS  Google Scholar 

  44. Chen LL, Carmichael GG (2009) Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. Mol Cell 35:467–478

    Article  PubMed  CAS  Google Scholar 

  45. Naganuma T, Nakagawa S, Tanigawa A, Sasaki YF, Goshima N, Hirose T (2012) Alternative 3′-end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J 31:4020–4034

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Anko ML, Muller-McNicoll M, Brandl H, Curk T, Gorup C, Henry I, Ule J, Neugebauer KM (2012) The RNA-binding landscapes of two SR proteins reveal unique functions and binding to diverse RNA classes. Genome Biol 13:R17

    Article  PubMed  Google Scholar 

  48. Sanford JR, Wang X, Mort M, Vanduyn N, Cooper DN, Mooney SD, Edenberg HJ, Liu Y (2009) Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts. Genome Res 19:381–394

    Article  PubMed  CAS  Google Scholar 

  49. Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD, Dorrestein PC, Rosenfeld MG (2011) ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147:773–788

    Article  PubMed  CAS  Google Scholar 

  50. Bourgeois CF, Lejeune F, Stevenin J (2004) Broad specificity of SR (serine/arginine) proteins in the regulation of alternative splicing of pre-messenger RNA. Prog Nucleic Acid Res Mol Biol 78:37–88

    Article  PubMed  CAS  Google Scholar 

  51. Long JC, Caceres JF (2009) The SR protein family of splicing factors: master regulators of gene expression. Biochem J 417:15–27

    Article  PubMed  CAS  Google Scholar 

  52. Lin R, Roychowdhury-Saha M, Black C, Watt AT, Marcusson EG, Freier SM, Edgington TS (2011) Control of RNA processing by a large non-coding RNA over-expressed in carcinomas. FEBS Lett 585:671–676

    Article  PubMed  CAS  Google Scholar 

  53. Cartegni L, Krainer AR (2003) Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat Struct Biol 10:120–125

    Article  PubMed  CAS  Google Scholar 

  54. Moroy T, Heyd F (2007) The impact of alternative splicing in vivo: mouse models show the way. RNA 13:1155–1171

    Article  PubMed  CAS  Google Scholar 

  55. Bernstein E, Duncan EM, Masui O, Gil J, Heard E, Allis CD (2006) Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol Cell Biol 26:2560–2569

    Article  PubMed  CAS  Google Scholar 

  56. Hu Q, Kwon YS, Nunez E, Cardamone MD, Hutt KR, Ohgi KA, Garcia-Bassets I, Rose DW, Glass CK, Rosenfeld MG et al (2008) Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules. Proc Natl Acad Sci U S A 105:19199–19204

    Article  PubMed  CAS  Google Scholar 

  57. Schuettengruber B, Martinez AM, Iovino N, Cavalli G (2011) Trithorax group proteins: switching genes on and keeping them active. Nat Rev Mol Cell Biol 12:799–814

    Article  PubMed  CAS  Google Scholar 

  58. Strahl BD, Grant PA, Briggs SD, Sun ZW, Bone JR, Caldwell JA, Mollah S, Cook RG, Shabanowitz J, Hunt DF et al (2002) Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol Cell Biol 22:1298–1306

    Article  PubMed  CAS  Google Scholar 

  59. Wagner EJ, Carpenter PB (2012) Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol 13:115–126

    Article  PubMed  CAS  Google Scholar 

  60. Lebedeva S, Jens M, Theil K, Schwanhausser B, Selbach M, Landthaler M, Rajewsky N (2011) Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR. Mol Cell 43:340–352

    Article  PubMed  CAS  Google Scholar 

  61. Li L, Feng T, Lian Y, Zhang G, Garen A, Song X (2009) Role of human noncoding RNAs in the control of tumorigenesis. Proc Natl Acad Sci U S A 106:12956–12961

    Article  PubMed  CAS  Google Scholar 

  62. Grippo PJ, Sandgren EP (2000) Highly invasive transitional cell carcinoma of the bladder in a simian virus 40 T-antigen transgenic mouse model. Am J Pathol 157:805–813

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We apologize to all scientists whose important work could not be cited in this review due to space constraints. Our research is supported by the German Research Foundation (DFG Transregio TRR77, TP B03), the Marie Curie Program of the European Commission, the Helmholtz Society (VH-NG-504), the Virtual Helmholtz Institute for Resistance in Leukemia, the German Cancer Research Center (DKFZ), and the Institute of Pathology, University of Heidelberg.

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The authors declare no conflict of interests.

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Authors and Affiliations

  1. Helmholtz-University-Group “Molecular RNA Biology & Cancer,” German Cancer Research Center DKFZ and Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Tony Gutschner, Monika Hämmerle & Sven Diederichs

  2. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280 (B150), 69120, Heidelberg, Germany

    Sven Diederichs

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  1. Tony Gutschner
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  2. Monika Hämmerle
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Correspondence to Sven Diederichs.

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Parts of this text have been included in the doctoral thesis of Tony Gutschner.

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Gutschner, T., Hämmerle, M. & Diederichs, S. MALAT1 — a paradigm for long noncoding RNA function in cancer. J Mol Med 91, 791–801 (2013). https://doi.org/10.1007/s00109-013-1028-y

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