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Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB


The long noncoding MALAT1 RNA is upregulated in cancer tissues and its elevated expression is associated with hyper-proliferation, but the underlying mechanism is poorly understood. We demonstrate that MALAT1 levels are regulated during normal cell cycle progression. Genome-wide transcriptome analyses in normal human diploid fibroblasts reveal that MALAT1 modulates the expression of cell cycle genes and is required for G1/S and mitotic progression. Depletion of MALAT1 leads to activation of p53 and its target genes. The cell cycle defects observed in MALAT1-depleted cells are sensitive to p53 levels, indicating that p53 is a major downstream mediator of MALAT1 activity. Furthermore, MALAT1-depleted cells display reduced expression of B-MYB (Mybl2), an oncogenic transcription factor involved in G2/M progression, due to altered binding of splicing factors on B-MYB pre-mRNA and aberrant alternative splicing. In human cells, MALAT1 promotes cellular proliferation by modulating the expression and/or pre-mRNA processing of cell cycle–regulated transcription factors. These findings provide mechanistic insights on the role of MALAT1 in regulating cellular proliferation.


Vyšlo v časopise: Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003368
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003368

Souhrn

The long noncoding MALAT1 RNA is upregulated in cancer tissues and its elevated expression is associated with hyper-proliferation, but the underlying mechanism is poorly understood. We demonstrate that MALAT1 levels are regulated during normal cell cycle progression. Genome-wide transcriptome analyses in normal human diploid fibroblasts reveal that MALAT1 modulates the expression of cell cycle genes and is required for G1/S and mitotic progression. Depletion of MALAT1 leads to activation of p53 and its target genes. The cell cycle defects observed in MALAT1-depleted cells are sensitive to p53 levels, indicating that p53 is a major downstream mediator of MALAT1 activity. Furthermore, MALAT1-depleted cells display reduced expression of B-MYB (Mybl2), an oncogenic transcription factor involved in G2/M progression, due to altered binding of splicing factors on B-MYB pre-mRNA and aberrant alternative splicing. In human cells, MALAT1 promotes cellular proliferation by modulating the expression and/or pre-mRNA processing of cell cycle–regulated transcription factors. These findings provide mechanistic insights on the role of MALAT1 in regulating cellular proliferation.


Zdroje

1. MattickJS (2009) The genetic signatures of noncoding RNAs. PLoS Genet 5: e1000459 doi:10.1371/journal.pgen.1000459

2. MattickJS, MakuninIV (2006) Non-coding RNA. Hum Mol Genet 15(Spec No 1): R17–29.

3. PrasanthKV, SpectorDL (2007) Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum. Genes Dev 21: 11–42.

4. RinnJL, ChangHY (2012) Genome Regulation by Long Noncoding RNAs. Annu Rev Biochem 81: 145–166.

5. AravinAA, HannonGJ, BrenneckeJ (2007) The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 318: 761–764.

6. GirardA, HannonGJ (2008) Conserved themes in small-RNA-mediated transposon control. Trends Cell Biol 18: 136–148.

7. KloostermanWP, PlasterkRH (2006) The diverse functions of microRNAs in animal development and disease. Dev Cell 11: 441–450.

8. PillaiRS, BhattacharyyaSN, FilipowiczW (2007) Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol 17: 118–126.

9. WangKC, ChangHY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43: 904–914.

10. WangX, SongX, GlassCK, RosenfeldMG (2011) The long arm of long noncoding RNAs: roles as sensors regulating gene transcriptional programs. Cold Spring Harb Perspect Biol 3: a003756.

11. AmaralPP, ClarkMB, GascoigneDK, DingerME, MattickJS (2011) lncRNAdb: a reference database for long noncoding RNAs. Nucleic Acids Res 39: D146–151.

12. CarninciP, HayashizakiY (2007) Noncoding RNA transcription beyond annotated genes. Curr Opin Genet Dev 17: 139–144.

13. GuttmanM, RinnJL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482: 339–346.

14. WiluszJE, SunwooH, SpectorDL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 23: 1494–1504.

15. ZongX, TripathiV, PrasanthKV (2011) RNA splicing control: yet another gene regulatory role for long nuclear noncoding RNAs. RNA Biol 8: 968–977.

16. AuguiS, NoraEP, HeardE (2011) Regulation of X-chromosome inactivation by the X-inactivation centre. Nature reviews Genetics 12: 429–442.

17. LeeJT (2010) The X as model for RNA's niche in epigenomic regulation. Cold Spring Harb Perspect Biol 2: a003749.

18. BraidottiG, BaubecT, PaulerF, SeidlC, SmrzkaO, et al. (2004) The Air noncoding RNA: an imprinted cis-silencing transcript. Cold Spring Harb Symp Quant Biol 69: 55–66.

19. NaganoT, FraserP (2011) No-Nonsense Functions for Long Noncoding RNAs. Cell 145: 178–181.

20. NaganoT, MitchellJA, SanzLA, PaulerFM, Ferguson-SmithAC, et al. (2008) The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322: 1717–1720.

21. ChenLL, CarmichaelGG (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.

22. ClemsonCM, HutchinsonJN, SaraSA, EnsmingerAW, FoxAH, et al. (2009) An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol Cell 33: 717–726.

23. SasakiYT, IdeueT, SanoM, MituyamaT, HiroseT (2009) MENepsilon/beta noncoding RNAs are essential for structural integrity of nuclear paraspeckles. Proc Natl Acad Sci U S A 106: 2525–2530.

24. SunwooH, DingerME, WiluszJE, AmaralPP, MattickJS, et al. (2009) MEN varepsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res 19: 347–359.

25. DingerME, AmaralPP, MercerTR, PangKC, BruceSJ, et al. (2008) Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res 18: 1433–1445.

26. MercerTR, DingerME, SunkinSM, MehlerMF, MattickJS (2008) Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A 105: 716–721.

27. RavasiT, SuzukiH, PangKC, KatayamaS, FurunoM, et al. (2006) Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res 16: 11–19.

28. GibbEA, VucicEA, EnfieldKS, StewartGL, LonerganKM, et al. (2011) Human cancer long non-coding RNA transcriptomes. PLoS ONE 6: e25915 doi:10.1371/journal.pone.0025915

29. HungT, WangY, LinMF, KoegelAK, KotakeY, et al. (2011) Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 43: 621–629.

30. AguiloF, ZhouMM, WalshMJ (2011) Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression. Cancer Res 71: 5365–5369.

31. BurdCE, JeckWR, LiuY, SanoffHK, WangZ, et al. (2010) Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet 6: e1001233 doi:10.1371/journal.pgen.1001233

32. KotakeY, NakagawaT, KitagawaK, SuzukiS, LiuN, et al. (2011) Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene 30: 1956–1962.

33. WangX, AraiS, SongX, ReichartD, DuK, et al. (2008) Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454: 126–130.

34. GutschnerT, DiederichsS (2012) The Hallmarks of Cancer: A long non-coding RNA point of view. RNA Biol 9: 703–719.

35. HuarteM, RinnJL (2010) Large non-coding RNAs: missing links in cancer? Hum Mol Genet 19: R152–161.

36. SilvaJM, BoczekNJ, BerresMW, MaX, SmithDI (2011) LSINCT5 is over expressed in breast and ovarian cancer and affects cellular proliferation. RNA Biol 8: 496–505.

37. SpizzoR, AlmeidaMI, ColombattiA, CalinGA (2012) Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene 31: 4577–4587.

38. TsaiMC, SpitaleRC, ChangHY (2011) Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res 71: 3–7.

39. GuptaRA, ShahN, WangKC, KimJ, HorlingsHM, et al. (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464: 1071–1076.

40. HuarteM, GuttmanM, FeldserD, GarberM, KoziolMJ, et al. (2010) A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142: 409–419.

41. ZhouY, ZhongY, WangY, ZhangX, BatistaDL, et al. (2007) Activation of p53 by MEG3 non-coding RNA. J Biol Chem 282: 24731–24742.

42. JiP, DiederichsS, WangW, BoingS, MetzgerR, 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.

43. BernardD, PrasanthKV, TripathiV, ColasseS, NakamuraT, et al. (2010) A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. Embo J 29: 3082–3093.

44. HutchinsonJN, EnsmingerAW, ClemsonCM, LynchCR, LawrenceJB, et al. (2007) A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 8: 39.

45. SpectorDL, LamondAI (2011) Nuclear speckles. Cold Spring Harb Perspect Biol 3.

46. AnkoML, Muller-McNicollM, BrandlH, CurkT, GorupC, et al. (2012) The RNA-binding landscapes of two SR proteins reveal unique functions and binding to diverse RNA classes. Genome Biol 13: R17.

47. PolymenidouM, Lagier-TourenneC, HuttKR, HuelgaSC, MoranJ, et al. (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nature neuroscience 14: 459–468.

48. SanfordJR, WangX, MortM, VanduynN, CooperDN, et al. (2009) Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts. Genome Res 19: 381–394.

49. TollerveyJR, CurkT, RogeljB, BrieseM, CeredaM, et al. (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nature neuroscience 14: 452–458.

50. TripathiV, EllisJD, ShenZ, SongDY, PanQ, et al. (2010) The Nuclear-Retained Noncoding RNA MALAT1 Regulates Alternative Splicing by Modulating SR Splicing Factor Phosphorylation. Mol Cell 39: 925–938.

51. SchorIE, LleresD, RissoGJ, PawellekA, UleJ, et al. (2012) Perturbation of chromatin structure globally affects localization and recruitment of splicing factors. PLoS ONE 7: e48084 doi:10.1371/journal.pone.0048084

52. LiL, FengT, LianY, ZhangG, GarenA, et al. (2009) Role of human noncoding RNAs in the control of tumorigenesis. Proc Natl Acad Sci U S A 106: 12956–12961.

53. GutschnerT, HammerleM, EissmannM, HsuJ, KimY, et al. (2012) The non-coding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res doi:10.1158/0008-5472

54. YangL, LinC, LiuW, ZhangJ, OhgiKA, et al. (2011) ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147: 773–788.

55. FreundA, LabergeRM, DemariaM, CampisiJ (2012) Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 23: 2066–2075.

56. ShimiT, Butin-IsraeliV, AdamSA, HamanakaRB, GoldmanAE, et al. (2011) The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev 25: 2579–2593.

57. OhtaniK, DeGregoriJ, LeoneG, HerendeenDR, KellyTJ, et al. (1996) Expression of the HsOrc1 gene, a human ORC1 homolog, is regulated by cell proliferation via the E2F transcription factor. Mol Cell Biol 16: 6977–6984.

58. NakagawaS, IpJY, ShioiG, TripathiV, ZongX, et al. (2012) Malat1 is not an essential component of nuclear speckles in mice. Rna 18: 1487–1499.

59. FlorenesVA, MaelandsmoGM, ForusA, AndreassenA, MyklebostO, et al. (1994) MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. Journal of the National Cancer Institute 86: 1297–1302.

60. ScheffnerM, MungerK, ByrneJC, HowleyPM (1991) The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A 88: 5523–5527.

61. GirardiAJ, WeinsteinD, MoorheadPS (1966) SV40 transformation of human diploid cells. A parallel study of viral and karyologic parameters. Annales medicinae experimentalis et biologiae Fenniae 44: 242–254.

62. StevauxO, DysonNJ (2002) A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 14: 684–691.

63. JoaquinM, WatsonRJ (2003) Cell cycle regulation by the B-Myb transcription factor. Cellular and molecular life sciences : CMLS 60: 2389–2401.

64. SadasivamS, DuanS, DeCaprioJA (2012) The MuvB complex sequentially recruits B-Myb and FOXM1 to promote mitotic gene expression. Genes Dev 26: 474–489.

65. ZhuW, GiangrandePH, NevinsJR (2004) E2Fs link the control of G1/S and G2/M transcription. Embo J 23: 4615–4626.

66. LinR, Roychowdhury-SahaM, BlackC, WattAT, MarcussonEG, et al. (2011) Control of RNA processing by a large non-coding RNA over-expressed in carcinomas. FEBS Lett 585: 671–676.

67. DownCF, MillourJ, LamEW, WatsonRJ (2012) Binding of FOXM1 to G2/M gene promoters is dependent upon B-Myb. Biochim Biophys Acta 1819: 855–862.

68. LamEW, RobinsonC, WatsonRJ (1992) Characterization and cell cycle-regulated expression of mouse B-myb. Oncogene 7: 1885–1890.

69. PerezDS, HoageTR, PritchettJR, Ducharme-SmithAL, HallingML, et al. (2008) Long, abundantly expressed non-coding transcripts are altered in cancer. Hum Mol Genet 17: 642–655.

70. GuoF, LiY, LiuY, WangJ, LiY, et al. (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.

71. LaiMC, YangZ, ZhouL, ZhuQQ, XieHY, et al. (2012) Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Medical oncology 29: 1810–1816.

72. LinR, MaedaS, LiuC, KarinM, EdgingtonTS (2007) A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 26: 851–858.

73. SchmidtLH, SpiekerT, KoschmiederS, HumbergJ, JungenD, 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. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 6: 1984–1992.

74. PanQ, ShaiO, LeeLJ, FreyBJ, BlencoweBJ (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40: 1413–1415.

75. WangET, SandbergR, LuoS, KhrebtukovaI, ZhangL, et al. (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456: 470–476.

76. VousdenKH, PrivesC (2009) Blinded by the Light: The Growing Complexity of p53. Cell 137: 413–431.

77. MolenaarJJ, EbusME, GeertsD, KosterJ, LamersF, et al. (2009) Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells. Proc Natl Acad Sci U S A 106: 12968–12973.

78. YenTJ, LiG, SchaarBT, SzilakI, ClevelandDW (1992) CENP-E is a putative kinetochore motor that accumulates just before mitosis. Nature 359: 536–539.

79. SchaarBT, ChanGK, MaddoxP, SalmonED, YenTJ (1997) CENP-E function at kinetochores is essential for chromosome alignment. J Cell Biol 139: 1373–1382.

80. WoodKW, SakowiczR, GoldsteinLS, ClevelandDW (1997) CENP-E is a plus end-directed kinetochore motor required for metaphase chromosome alignment. Cell 91: 357–366.

81. WhitfieldML, GeorgeLK, GrantGD, PerouCM (2006) Common markers of proliferation. Nat Rev Cancer 6: 99–106.

82. SalaA (2005) B-MYB, a transcription factor implicated in regulating cell cycle, apoptosis and cancer. Eur J Cancer 41: 2479–2484.

83. ThornerAR, HoadleyKA, ParkerJS, WinkelS, MillikanRC, et al. (2009) In vitro and in vivo analysis of B-Myb in basal-like breast cancer. Oncogene 28: 742–751.

84. EissmannM, GutschnerT, HammerleM, GuntherS, Caudron-HergerM, et al. (2012) Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development. RNA Biol 9: 1076–1087.

85. ZhangB, ArunG, MaoYS, LazarZ, HungG, et al. (2012) The lncRNA Malat1 Is Dispensable for Mouse Development but Its Transcription Plays a cis-Regulatory Role in the Adult. Cell reports 2: 111–123.

86. RinnJL, KerteszM, WangJK, SquazzoSL, XuX, et al. (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129: 1311–1323.

87. TsaiMC, ManorO, WanY, MosammaparastN, WangJK, et al. (2010) Long noncoding RNA as modular scaffold of histone modification complexes. Science 329: 689–693.

88. SchorderetP, DubouleD (2011) Structural and functional differences in the long non-coding RNA hotair in mouse and human. PLoS Genet 7: e1002071 doi:10.1371/journal.pgen.1002071

89. BerthetC, AleemE, CoppolaV, TessarolloL, KaldisP (2003) Cdk2 knockout mice are viable. Current biology : CB 13: 1775–1785.

90. OrtegaS, PrietoI, OdajimaJ, MartinA, DubusP, et al. (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35: 25–31.

91. CaiD, LathamVMJr, ZhangX, ShapiroGI (2006) Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res 66: 9270–9280.

92. ChungJH, BunzF (2010) Cdk2 is required for p53-independent G2/M checkpoint control. PLoS Genet 6: e1000863 doi:10.1371/journal.pgen.1000863

93. DuJ, WidlundHR, HorstmannMA, RamaswamyS, RossK, et al. (2004) Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 6: 565–576.

94. LongXE, GongZH, PanL, ZhongZW, LeYP, et al. (2010) Suppression of CDK2 expression by siRNA induces cell cycle arrest and cell proliferation inhibition in human cancer cells. BMB reports 43: 291–296.

95. TetsuO, McCormickF (2003) Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3: 233–245.

96. KalaszczynskaI, GengY, IinoT, MizunoS, ChoiY, et al. (2009) Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells. Cell 138: 352–365.

97. LiuDX, GreeneLA (2001) Regulation of neuronal survival and death by E2F-dependent gene repression and derepression. Neuron 32: 425–438.

98. SantilliG, SchwabR, WatsonR, EbertC, AronowBJ, et al. (2005) Temperature-dependent modification and activation of B-MYB: implications for cell survival. J Biol Chem 280: 15628–15634.

99. GuffantiA, IaconoM, PelucchiP, KimN, SoldaG, et al. (2009) A transcriptional sketch of a primary human breast cancer by 454 deep sequencing. BMC Genomics 10: 163.

100. GutschnerT, BaasM, DiederichsS (2011) Noncoding RNA gene silencing through genomic integration of RNA destabilizing elements using zinc finger nucleases. Genome Res 21: 1944–1954.

101. CheadleC, VawterMP, FreedWJ, BeckerKG (2003) Analysis of microarray data using Z score transformation. The Journal of molecular diagnostics : JMD 5: 73–81.

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