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The LncRNA HOTAIR-expression, regulation and function in cancer

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Abstract

Only 2% of transcribed RNAs encode proteins. Whole transcriptome analysis suggests that a predominant number of transcripts synthesized in the cell are non-coding RNAs (ncRNAs). Classical noncoding RNAs comprise housekeeping structural RNAs like transfer RNAs and ribosomal RNAs. More recently, two types of ncRNAs with regulatory function in specialized, cell specific processes have been discovered. They fall into small/short ncRNAs and long non-coding RNAs (lncRNAs). While small ncRNAs typically function in protein translation, lncRNAs seem to be more versatile, abundant at specific developmental stages, and diverse in function. They epigenetically remodel the genome, regulate gene expression, are major scaffolding RNAs within protein complexes, and are often themselves regulated by complex mechanisms. One such lncRNA is HOTAIR, that not only plays key roles in development and body axis patterning but also promotes cancer progression when dysregulated in the adult. This review discusses the multiple molecular functions of HOTAIR with special emphasis on cancer.

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References

  1. Amort T, Souliere MF, Wille A, Jia XY, Fiegl H, Worle H, et al. Long non-coding RNAs as targets for cytosine methylation. RNA Biol. 2013;10(6):1003–8.

    Article  PubMed  Google Scholar 

  2. Ballas N, Battaglioli E, Atouf F, Andres ME, Chenoweth J, Anderson ME, et al. Regulation of neuronal traits by a novel transcriptional complex. Neuron. 2001;31(3):353–65.

    Article  CAS  PubMed  Google Scholar 

  3. Bayram S, Sumbul AT, Batmaci CY, Genc A. Effect of HOTAIR rs920778 polymorphism on breast cancer susceptibility and clinicopathologic features in a Turkish population. Tumour Biol. 2015;36(5):3863–70.

    Article  CAS  PubMed  Google Scholar 

  4. Bernstein E, Allis CD. RNA meets chromatin. Genes Dev. 2005;19(14):1635–55.

    Article  CAS  PubMed  Google Scholar 

  5. Bhan A, Hussain I, Ansari KI, Bobzean SA, Perrotti LI, Mandal SS. Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo. J Steroid Biochem Mol Biol. 2014;141:160–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bhan A, Hussain I, Ansari KI, Kasiri S, Bashyal A, Mandal SS. Antisense transcript long noncoding RNA (lncRNA) HOTAIR is transcriptionally induced by estradiol. J Mol Biol. 2013;425(19):3707–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bian EB, Ma CC, He XJ, Wang C, Zong G, Wang HL et al. Epigenetic modification of miR-141 regulates SKA2 by an endogenous ‘sponge’ HOTAIR in glioma. Oncotarget. 2016.

  8. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447(7146):799–816.

    Article  CAS  PubMed  Google Scholar 

  9. Brennan CM, Steitz JA. HuR and mRNA stability. Cell Mol Life Sci. 2001;58(2):266–77.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cai B, Wu Z, Liao K, Zhang S. Long noncoding RNA HOTAIR can serve as a common molecular marker for lymph node metastasis: a meta-analysis. Tumour Biol. 2014;35(9):8445–50.

    Article  CAS  PubMed  Google Scholar 

  12. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, et al. The transcriptional landscape of the mammalian genome. Science. 2005;309(5740):1559–63.

    Article  CAS  PubMed  Google Scholar 

  13. Chen J, Lin C, Yong W, Ye Y, Huang Z. Calycosin and genistein induce apoptosis by inactivation of HOTAIR/p-Akt signaling pathway in human breast cancer MCF-7 cells. Cell Physiol Biochem. 2015;35(2):722–8.

    Article  CAS  PubMed  Google Scholar 

  14. Chisholm KM, Wan Y, Li R, Montgomery KD, Chang HY, West RB. Detection of long non-coding RNA in archival tissue: correlation with polycomb protein expression in primary and metastatic breast carcinoma. PLoS ONE. 2012;7(10):e47998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chiyomaru T, Fukuhara S, Saini S, Majid S, Deng G, Shahryari V, et al. Long non-coding RNA HOTAIR is targeted and regulated by miR-141 in human cancer cells. J Biol Chem. 2014;289(18):12550–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Corkery B, Crown J, Clynes M, O’Donovan N. Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Ann Oncol. 2009;20(5):862–7.

    Article  CAS  PubMed  Google Scholar 

  17. Dong L, Hui L. HOTAIR promotes proliferation, migration, and invasion of ovarian cancer SKOV3 cells through regulating PIK3R3. Med Sci Monit. 2016;22:325–31.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Du M, Wang W, Jin H, Wang Q, Ge Y, Lu J, et al. The association analysis of lncRNA HOTAIR genetic variants and gastric cancer risk in a Chinese population. Oncotarget. 2015;6(31):31255–62.

    PubMed  PubMed Central  Google Scholar 

  19. Geng YJ, Xie SL, Li Q, Ma J, Wang GY. Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res. 2011;39(6):2119–28.

    Article  CAS  PubMed  Google Scholar 

  20. Guo W, Dong Z, Bai Y, Guo Y, Shen S, Kuang G, et al. Associations between polymorphisms of HOTAIR and risk of gastric cardia adenocarcinoma in a population of north China. Tumour Biol. 2015;36(4):2845–54.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hajjari M, Salavaty A. HOTAIR: an oncogenic long non-coding RNA in different cancers. Cancer Biol Med. 2015;12(1):1–9.

    PubMed  PubMed Central  Google Scholar 

  23. Kaneko S, Li G, Son J, Xu CF, Margueron R, Neubert TA, et al. Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA. Genes Dev. 2010;24(23):2615–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ke J, Yao YL, Zheng J, Wang P, Liu YH, Ma J, et al. Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-326. Oncotarget. 2015;6(26):21934–49.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kim HJ, Lee DW, Yim GW, Nam EJ, Kim S, Kim SW, et al. Long non-coding RNA HOTAIR is associated with human cervical cancer progression. Int J Oncol. 2015;46(2):521–30.

    CAS  PubMed  Google Scholar 

  26. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lappin TR, Grier DG, Thompson A, Halliday HL. HOX genes: seductive science, mysterious mechanisms. Ulster Med J. 2006;75(1):23–31.

    PubMed  PubMed Central  Google Scholar 

  28. 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 Pathol. 2013;182(1):64–70.

    Article  CAS  Google Scholar 

  29. Li H, An J, Wu M, Zheng Q, Gui X, Li T, et al. LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Oncotarget. 2015;6(29):27847–64.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Li J, Yang S, Su N, Wang Y, Yu J, Qiu H, et al. Overexpression of long non-coding RNA HOTAIR leads to chemoresistance by activating the Wnt/beta-catenin pathway in human ovarian cancer. Tumour Biol. 2016;37(2):2057–65.

    Article  CAS  PubMed  Google Scholar 

  31. Li JT, Wang LF, Zhao YL, Yang T, Li W, Zhao J, et al. Nuclear factor of activated T cells 5 maintained by Hotair suppression of miR-568 upregulates S100 calcium binding protein A4 to promote breast cancer metastasis. Breast Cancer Res. 2014;16(5):454.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lin J, Arlinghaus R. Activated c-Abl tyrosine kinase in malignant solid tumors. Oncogene. 2008;27(32):4385–91.

    Article  CAS  PubMed  Google Scholar 

  33. Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu YW, Sun M, Xia R, Zhang EB, Liu XH, Zhang ZH, et al. LincHOTAIR epigenetically silences miR34a by binding to PRC2 to promote the epithelial-to-mesenchymal transition in human gastric cancer. Cell Death Dis. 2015;6:e1802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W, et al. The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS ONE. 2013;8(10):e77293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu L, Zhu G, Zhang C, Deng Q, Katsaros D, Mayne ST, et al. Association of large noncoding RNA HOTAIR expression and its downstream intergenic CpG island methylation with survival in breast cancer. Breast Cancer Res Treat. 2012;136(3):875–83.

    Article  CAS  PubMed  Google Scholar 

  37. Ma MZ, Li CX, Zhang Y, Weng MZ, Zhang MD, Qin YY, et al. Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol Cancer. 2014;13:156.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Milevskiy MJ, Al-Ejeh F, Saunus JM, Northwood KS, Bailey PJ, Betts JA, et al. Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer. Hum Mol Genet. 2016;25(15):3269–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ozes AR, Miller DF, Ozes ON, Fang F, Liu Y, Matei D et al. NF-kappaB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer. Oncogene. 2016.

  41. Pan W, Liu L, Wei J, Ge Y, Zhang J, Chen H, et al. A functional lncRNA HOTAIR genetic variant contributes to gastric cancer susceptibility. Mol Carcinog. 2016;55(1):90–6.

    Article  CAS  PubMed  Google Scholar 

  42. Pastori C, Kapranov P, Penas C, Peschansky V, Volmar CH, Sarkaria JN, et al. The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. Pro Natl Acad Sci. 2015;112(27):8326–31.

    Article  CAS  Google Scholar 

  43. Pauli A, Rinn JL, Schier AF. Non-coding RNAs as regulators of embryogenesis. Nat Rev Genet. 2011;12(2):136–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pelengaris S, Khan M, Evan G. c-MYC: more than just a matter of life and death. Nat Rev Cancer. 2002;2(10):764–76.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Robinson JL, Carroll JS. FoxA1 is a key mediator of hormonal response in breast and prostate cancer. Front Endocrinol. 2012;3:68.

    Article  CAS  Google Scholar 

  47. Schuettengruber B, Cavalli G. Recruitment of polycomb group complexes and their role in the dynamic regulation of cell fate choice. Development. 2009;136(21):3531–42.

    Article  CAS  PubMed  Google Scholar 

  48. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941–53.

    Article  CAS  PubMed  Google Scholar 

  49. Shi YJ, Matson C, Lan F, Iwase S, Baba T, Shi Y. Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell. 2005;19(6):857–64.

    Article  CAS  PubMed  Google Scholar 

  50. Somarowthu S, Legiewicz M, Chillon I, Marcia M, Liu F, Pyle AM. HOTAIR forms an intricate and modular secondary structure. Mol Cell. 2015;58(2):353–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sorensen KP, Thomassen M, Tan Q, Bak M, Cold S, Burton M, et al. Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer. Breast Cancer Res Treat. 2013;142(3):529–36.

    Article  PubMed  Google Scholar 

  52. Su X, Malouf GG, Chen Y, Zhang J, Yao H, Valero V, et al. Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. Oncotarget. 2014;5(20):9864–76.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Tang L, Shen H, Li X, Li Z, Liu Z, Xu J, et al. MiR-125a-5p decreases after long non-coding RNA HOTAIR knockdown to promote cancer cell apoptosis by releasing caspase 2. Cell Death Dis. 2016;7:e2137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Teschendorff AE, Lee SH, Jones A, Fiegl H, Kalwa M, Wagner W, et al. HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer. Genome Med. 2015;7(1):108.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 2016;17(5):272–83.

    Article  CAS  PubMed  Google Scholar 

  56. Tian T, Li C, Xiao J, Shen Y, Lu Y, Jiang L, et al. Quantitative assessment of the polymorphisms in the HOTAIR lncRNA and cancer risk: a meta-analysis of 8 case-control studies. PLoS ONE. 2016;11(3):e0152296.

    Article  PubMed  PubMed Central  Google Scholar 

  57. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wahlestedt C. Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat Rev Drug Discov. 2013;12(6):433–46.

    Article  CAS  PubMed  Google Scholar 

  60. Wang L, Zeng X, Chen S, Ding L, Zhong J, Zhao JC, et al. BRCA1 is a negative modulator of the PRC2 complex. EMBO J. 2013;32(11):1584–97.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Wang YL, Overstreet AM, Chen MS, Wang J, Zhao HJ, Ho PC, et al. Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR. Oncotarget. 2015;6(13):11150–61.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Xue X, Yang YA, Zhang A, Fong KW, Kim J, Song B et al. LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene. 2015.

  63. Xue Y, Gu D, Ma G, Zhu L, Hua Q, Chu H, et al. Genetic variants in lncRNA HOTAIR are associated with risk of colorectal cancer. Mutagenesis. 2015;30(2):303–10.

    Article  CAS  PubMed  Google Scholar 

  64. Yan R, Cao J, Song C, Chen Y, Wu Z, Wang K, et al. Polymorphisms in lncRNA HOTAIR and susceptibility to breast cancer in a Chinese population. Cancer Epidemiol. 2015;39(6):978–85.

    Article  PubMed  Google Scholar 

  65. Yang G, Zhang S, Gao F, Liu Z, Lu M, Peng S, et al. Osteopontin enhances the expression of HOTAIR in cancer cells via IRF1. Biochim Biophys Acta. 2014;1839(9):837–48.

    Article  CAS  PubMed  Google Scholar 

  66. Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18(5):1243–50.

    Article  PubMed  Google Scholar 

  67. Yao Y, Li J, Wang L. Large intervening non-coding RNA HOTAIR is an indicator of poor prognosis and a therapeutic target in human cancers. Int J Mol Sci. 2014;15(10):18985–99.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Yiwei T, Hua H, Hui G, Mao M, Xiang L. HOTAIR interacting with MAPK1 regulates ovarian cancer skov3 cell proliferation, migration, and invasion. Med Sci Monit. 2015;21:1856–63.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Yoon JH, Abdelmohsen K, Kim J, Yang X, Martindale JL, Tominaga-Yamanaka K, et al. Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination. Nat Commun. 2013;4:2939.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Zhang A, Zhao JC, Kim J, Fong KW, Yang YA, Chakravarti D, et al. LncRNA HOTAIR enhances the androgen-receptor-mediated transcriptional program and drives castration-resistant prostate cancer. Cell Rep. 2015;13(1):209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, et al. MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells. 2014;32(11):2858–68.

    Article  CAS  PubMed  Google Scholar 

  72. Zhang J, Zhang P, Wang L, Piao HL, Ma L. Long non-coding RNA HOTAIR in carcinogenesis and metastasis. Acta Biochim Biophys Sinica. 2014;46(1):1–5.

    Article  Google Scholar 

  73. Zhang K, Sun X, Zhou X, Han L, Chen L, Shi Z, et al. Long non-coding RNA HOTAIR promotes glioblastoma cell cycle progression in an EZH2 dependent manner. Oncotarget. 2015;6(1):537–46.

    Article  PubMed  Google Scholar 

  74. Zhang X, Zhou L, Fu G, Sun F, Shi J, Wei J, et al. The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNA HOTAIR via a novel intronic enhancer. Carcinogenesis. 2014;35(9):2062–7.

    Article  CAS  PubMed  Google Scholar 

  75. Zhang ZX, Tong X, Zhang WN, Fu WN. Association between the HOTAIR polymorphisms and cancer risk: an updated meta-analysis. Oncotarget. 2016.

  76. Zhou C, Ye L, Jiang C, Bai J, Chi Y, Zhang H. Long noncoding RNA HOTAIR, a hypoxia-inducible factor-1alpha activated driver of malignancy, enhances hypoxic cancer cell proliferation, migration, and invasion in non-small cell lung cancer. Tumour Biol. 2015;36(12):9179–88.

    Article  CAS  PubMed  Google Scholar 

  77. Zhou X, Ren Y, Zhang J, Zhang C, Zhang K, Han L, et al. HOTAIR is a therapeutic target in glioblastoma. Oncotarget. 2015;6(10):8353–65.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Zhuang Y, Wang X, Nguyen HT, Zhuo Y, Cui X, Fewell C, et al. Induction of long intergenic non-coding RNA HOTAIR in lung cancer cells by type I collagen. J Hematol Oncol. 2013;6:35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Rahul P. Bakshi and Dr. Sumantra Chatterjee for critical comments and useful suggestions on this manuscript. Ms. Antara Biswas is funded by Department of Biotechnology (DBT-JRF/2012-13/297), India.

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  1. National Institute of Biomedical Genomics, P.O. N.S.S, Kalyani, West Bengal, 741251, India

    Antara Biswas & Kartiki V. Desai

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This article is based on the presentation made during the 17th All India Congress of Cytology and Genetics and International Symposium on “Exploring Genomes: The New Frontier” held at CSIR-Indian Institute of Chemical biology, Kolkata in collaboration with Archana Sharma Foundation of Calcutta during December 22–24, 2015.

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Biswas, A., Desai, K.V. The LncRNA HOTAIR-expression, regulation and function in cancer. Nucleus 60, 155–164 (2017). https://doi.org/10.1007/s13237-017-0201-z

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