Advertisement

Cancer and Metastasis Reviews

, Volume 35, Issue 2, pp 235–262 | Cite as

Deciphering the function of non-coding RNAs in prostate cancer

  • João Ramalho-Carvalho
  • Bastian Fromm
  • Rui Henrique
  • Carmen Jerónimo
NON-THEMATIC REVIEW

Abstract

The advent of next-generation sequencing methods is fuelling the discovery of multiple non-coding RNA transcripts with direct implication in cell biology and homeostasis. This new layer of biological regulation seems to be of particular importance in human pathogenesis, including cancer. The aberrant expression of ncRNAs is a feature of prostate cancer, as they promote tumor-suppressive or oncogenic activities, controlling multicellular events leading to carcinogenesis and tumor progression. From the small RNAs involved in the RNAi pathway to the long non-coding RNAs controlling chromatin remodeling, alternative splicing, and DNA repair, the non-coding transcriptome represents the significant majority of transcriptional output. As such, ncRNAs appear as exciting new diagnostic, prognostic, and therapeutic tools. However, additional work is required to characterize the RNA species, their functions, and their applicability to clinical practice in oncology. In this review, we summarize the most important features of ncRNA biology, emphasizing its relevance in prostate carcinogenesis and its potential for clinical applications.

Keywords

ncRNA microRNA lncRNA Prostate cancer Transcription 

Notes

Acknowledgments

The authors would like to acknowledge the scientific input provided by Rui Lopes. This work was funded by research grants from Research Center of Portuguese Oncology Institute – Porto (CI-IPOP 4–2012) and by Federal funds through Programa Operacional Temático Factores de Competitividade (COMPETE) with co-participation from the European Community Fund (FEDER) and by national funds through Fundação para a Ciência e Tecnología (FCT) under the projects EXPL/BIM-ONC/0556/2012. JR-C is supported by FCT-Fundação para a Ciência e a Tecnologia grant (SFRH/BD/71293/2010). BF is supported by the South-Eastern Norway Regional Health Authority grant #2014041.

References

  1. 1.
    Ling, H., Vincent, K., Pichler, M., Fodde, R., Berindan-Neagoe, I., Slack, F. J., et al. (2015). Junk DNA and the long non-coding RNA twist in cancer genetics. Oncogene. doi: 10.1038/onc.2014.456.PubMedCentralGoogle Scholar
  2. 2.
    Rinn, J. L., & Chang, H. Y. (2012). Genome regulation by long noncoding RNAs. Annual Review of Biochemistry, 81, 145–166. doi: 10.1146/annurev-biochem-051410-092902.PubMedCrossRefGoogle Scholar
  3. 3.
    Hoagland, M. B., Stephenson, M. L., Scott, J. F., Hecht, L. I., & Zamecnik, P. C. (1958). A soluble ribonucleic acid intermediate in protein synthesis. Journal of Biological Chemistry, 231(1), 241–257.PubMedGoogle Scholar
  4. 4.
    Palade, G. E. (1955). A small particulate component of the cytoplasm. Journal of Biophysical and Biochemical Cytology, 1(1), 59–68.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Consortium, E. P, Bernstein, B. E., Birney, E., Dunham, I., Green, E. D., Gunter, C., et al. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489(7414), 57–74. doi: 10.1038/nature11247.CrossRefGoogle Scholar
  6. 6.
    Ma, W., Ay, F., Lee, C., Gulsoy, G., Deng, X., Cook, S., et al. (2015). Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes. Nature Methods, 12(1), 71–78. doi: 10.1038/nmeth.3205.PubMedCrossRefGoogle Scholar
  7. 7.
    Kapranov, P., Cheng, J., Dike, S., Nix, D. A., Duttagupta, R., Willingham, A. T., et al. (2007). RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science, 316(5830), 1484–1488. doi: 10.1126/science.1138341.PubMedCrossRefGoogle Scholar
  8. 8.
    Nord, A. S., Blow, M. J., Attanasio, C., Akiyama, J. A., Holt, A., Hosseini, R., et al. (2013). Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell, 155(7), 1521–1531. doi: 10.1016/j.cell.2013.11.033.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Flynn, R. A., & Chang, H. Y. (2012). Active chromatin and noncoding RNAs: an intimate relationship. Current Opinion in Genetics and Development, 22(2), 172–178. doi: 10.1016/j.gde.2011.11.002.PubMedCrossRefGoogle Scholar
  10. 10.
    Rinn, J., & Guttman, M. (2014). RNA Function. RNA and dynamic nuclear organization. Science, 345(6202), 1240–1241. doi: 10.1126/science.1252966.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., et al. (2012). Landscape of transcription in human cells. Nature, 489(7414), 101–108. doi: 10.1038/nature11233.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Mattick, J. S., & Rinn, J. L. (2015). Discovery and annotation of long noncoding RNAs. Nature Structural & Molecular Biology, 22(1), 5–7. doi: 10.1038/nsmb.2942.CrossRefGoogle Scholar
  13. 13.
    Derrien, T., Johnson, R., Bussotti, G., Tanzer, A., Djebali, S., Tilgner, H., et al. (2012). The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Research, 22(9), 1775–1789. doi: 10.1101/gr.132159.111.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Le Thomas, A., Rogers, A. K., Webster, A., Marinov, G. K., Liao, S. E., Perkins, E. M., et al. (2013). Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state. Genes and Development, 27(4), 390–399. doi: 10.1101/gad.209841.112.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Fang, W., & Bartel, D. P. (2015). The menu of features that define primary MicroRNAs and enable de novo design of MicroRNA genes. Molecular Cell, 60(1), 131–145. doi: 10.1016/j.molcel.2015.08.015.PubMedCrossRefGoogle Scholar
  16. 16.
    Mercer, T. R., & Mattick, J. S. (2013). Structure and function of long noncoding RNAs in epigenetic regulation. Nature Structural & Molecular Biology, 20(3), 300–307. doi: 10.1038/nsmb.2480.CrossRefGoogle Scholar
  17. 17.
    Raj, A., & van Oudenaarden, A. (2008). Nature, nurture, or chance: stochastic gene expression and its consequences. Cell, 135(2), 216–226. doi: 10.1016/j.cell.2008.09.050.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Graur, D., Zheng, Y., Price, N., Azevedo, R. B., Zufall, R. A., & Elhaik, E. (2013). On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biology and Evolution, 5(3), 578–590. doi: 10.1093/gbe/evt028.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Ulitsky, I., & Bartel, D. P. (2013). lincRNAs: genomics, evolution, and mechanisms. Cell, 154(1), 26–46. doi: 10.1016/j.cell.2013.06.020.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Hezroni, H., Koppstein, D., Schwartz, M. G., Avrutin, A., Bartel, D. P., & Ulitsky, I. (2015). Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species. Cell Reports, 11(7), 1110–1122. doi: 10.1016/j.celrep.2015.04.023.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Qureshi, I. A., & Mehler, M. F. (2012). Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nature Review Neuroscience, 13(8), 528–541. doi: 10.1038/nrn3234.CrossRefGoogle Scholar
  22. 22.
    Gupta, R. A., Shah, N., Wang, K. C., Kim, J., Horlings, H. M., Wong, D. J., et al. (2010). Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature, 464(7291), 1071–1076. doi: 10.1038/nature08975.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Guil, S., Soler, M., Portela, A., Carrere, J., Fonalleras, E., Gomez, A., et al. (2012). Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nature Structural & Molecular Biology, 19(7), 664–670. doi: 10.1038/nsmb.2315.CrossRefGoogle Scholar
  24. 24.
    Boque-Sastre, R., Soler, M., Oliveira-Mateos, C., Portela, A., Moutinho, C., Sayols, S., et al. (2015). Head-to-head antisense transcription and R-loop formation promotes transcriptional activation. Proceedings of the National Academy of Sciences of the United States of America, 112(18), 5785–5790. doi: 10.1073/pnas.1421197112.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Calin, G. A., Dumitru, C. D., Shimizu, M., Bichi, R., Zupo, S., Noch, E., et al. (2002). Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America, 99(24), 15524–15529. doi: 10.1073/pnas.242606799.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Fu, A., Jacobs, D. I., Hoffman, A. E., Zheng, T., & Zhu, Y. (2015). PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome. Carcinogenesis, 36(10), 1094–1102. doi: 10.1093/carcin/bgv105.PubMedCrossRefGoogle Scholar
  27. 27.
    Bolton, E. M., Tuzova, A. V., Walsh, A. L., Lynch, T., & Perry, A. S. (2014). Noncoding RNAs in prostate cancer: the long and the short of it. Clinical Cancer Research, 20(1), 35–43. doi: 10.1158/1078-0432.CCR-13-1989.PubMedCrossRefGoogle Scholar
  28. 28.
    Steitz, J. A., & Tycowski, K. T. (1995). Small RNA chaperones for ribosome biogenesis. Science, 270(5242), 1626–1627.PubMedCrossRefGoogle Scholar
  29. 29.
    Kelly, B. D., Miller, N., Sweeney, K. J., Durkan, G. C., Rogers, E., Walsh, K., et al. (2015). A circulating MicroRNA signature as a biomarker for prostate cancer in a high risk group. Journal of Clinical Medicine, 4(7), 1369–1379. doi: 10.3390/jcm4071369.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Prensner, J. R., & Chinnaiyan, A. M. (2011). The emergence of lncRNAs in cancer biology. Cancer Discovery, 1(5), 391–407. doi: 10.1158/2159-8290.CD-11-0209.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Affymetrix, E. T. P., & Cold Spring Harbor Laboratory, E. T. P. (2009). Post-transcriptional processing generates a diversity of 5’-modified long and short RNAs. Nature, 457(7232), 1028–1032. doi: 10.1038/nature07759.CrossRefGoogle Scholar
  32. 32.
    Ghildiyal, M., & Zamore, P. D. (2009). Small silencing RNAs: an expanding universe. Nature Reviews Genetics, 10(2), 94–108. doi: 10.1038/nrg2504.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Nguyen, T. A., Jo, M. H., Choi, Y. G., Park, J., Kwon, S. C., Hohng, S., et al. (2015). Functional anatomy of the human microprocessor. Cell, 161(6), 1374–1387. doi: 10.1016/j.cell.2015.05.010.PubMedCrossRefGoogle Scholar
  34. 34.
    Wilson, R. C., Tambe, A., Kidwell, M. A., Noland, C. L., Schneider, C. P., & Doudna, J. A. (2015). Dicer-TRBP complex formation ensures accurate mammalian microRNA biogenesis. Molecular Cell, 57(3), 397–407. doi: 10.1016/j.molcel.2014.11.030.PubMedCrossRefGoogle Scholar
  35. 35.
    Ha, M., & Kim, V. N. (2014). Regulation of microRNA biogenesis. Nature Reviews Molecular Cell Biology, 15(8), 509–524. doi: 10.1038/nrm3838.PubMedCrossRefGoogle Scholar
  36. 36.
    Fromm, B., Billipp, T., Peck, L. E., Johansen, M., Tarver, J. E., King, B. L., et al. (2015). A uniform system for the annotation of vertebrate microRNA genes and the evolution of the human microRNAome. Annual Review of Genetics, 49, 213–242. doi: 10.1146/annurev-genet-120213-092023.PubMedCrossRefGoogle Scholar
  37. 37.
    Yang, J. S., & Lai, E. C. (2011). Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Molecular Cell, 43(6), 892–903. doi: 10.1016/j.molcel.2011.07.024.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Cheloufi, S., Dos Santos, C. O., Chong, M. M., & Hannon, G. J. (2010). A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature, 465(7298), 584–589. doi: 10.1038/nature09092.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Schirle, N. T., Sheu-Gruttadauria, J., & MacRae, I. J. (2014). Structural basis for microRNA targeting. Science, 346(6209), 608–613. doi: 10.1126/science.1258040.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hafner, M., Landthaler, M., Burger, L., Khorshid, M., Hausser, J., Berninger, P., et al. (2010). Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell, 141(1), 129–141. doi: 10.1016/j.cell.2010.03.009.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Baek, D., Villen, J., Shin, C., Camargo, F. D., Gygi, S. P., & Bartel, D. P. (2008). The impact of microRNAs on protein output. Nature, 455(7209), 64–71. doi: 10.1038/nature07242.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hausser, J., & Zavolan, M. (2014). Identification and consequences of miRNA-target interactions—beyond repression of gene expression. Nature Reviews Genetics, 15(9), 599–612. doi: 10.1038/nrg3765.PubMedCrossRefGoogle Scholar
  43. 43.
    Wyman, S. K., Knouf, E. C., Parkin, R. K., Fritz, B. R., Lin, D. W., Dennis, L. M., et al. (2011). Post-transcriptional generation of miRNA variants by multiple nucleotidyl transferases contributes to miRNA transcriptome complexity. Genome Research, 21(9), 1450–1461. doi: 10.1101/gr.118059.110.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Koppers-Lalic, D., Hackenberg, M., Bijnsdorp, I. V., van Eijndhoven, M. A., Sadek, P., Sie, D., et al. (2014). Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Reports, 8(6), 1649–1658. doi: 10.1016/j.celrep.2014.08.027.PubMedCrossRefGoogle Scholar
  45. 45.
    Chiang, H. R., Schoenfeld, L. W., Ruby, J. G., Auyeung, V. C., Spies, N., Baek, D., et al. (2010). Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes and Development, 24(10), 992–1009. doi: 10.1101/gad.1884710.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Berezikov, E., van Tetering, G., Verheul, M., van de Belt, J., van Laake, L., Vos, J., et al. (2006). Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis. Genome Research, 16(10), 1289–1298. doi: 10.1101/gr.5159906.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kim, V. N., Han, J., & Siomi, M. C. (2009). Biogenesis of small RNAs in animals. Nature Reviews Molecular Cell Biology, 10(2), 126–139. doi: 10.1038/nrm2632.PubMedCrossRefGoogle Scholar
  48. 48.
    Ghildiyal, M., Seitz, H., Horwich, M. D., Li, C., Du, T., Lee, S., et al. (2008). Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells. Science, 320(5879), 1077–1081. doi: 10.1126/science.1157396.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Okamura, K., Chung, W. J., Ruby, J. G., Guo, H., Bartel, D. P., & Lai, E. C. (2008). The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs. Nature, 453(7196), 803–806. doi: 10.1038/nature07015.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Cox, D. N., Chao, A., Baker, J., Chang, L., Qiao, D., & Lin, H. (1998). A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes and Development, 12(23), 3715–3727.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Peng, J. C., & Lin, H. (2013). Beyond transposons: the epigenetic and somatic functions of the Piwi-piRNA mechanism. Current Opinion in Cell Biology, 25(2), 190–194. doi: 10.1016/j.ceb.2013.01.010.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Grimson, A., Srivastava, M., Fahey, B., Woodcroft, B. J., Chiang, H. R., King, N., et al. (2008). Early origins and evolution of microRNAs and Piwi-interacting RNAs in animals. Nature, 455(7217), 1193–1197. doi: 10.1038/nature07415.PubMedCrossRefGoogle Scholar
  53. 53.
    Kim, V. N. (2006). Small RNAs just got bigger: Piwi-interacting RNAs (piRNAs) in mammalian testes. Genes and Development, 20(15), 1993–1997. doi: 10.1101/gad.1456106.PubMedCrossRefGoogle Scholar
  54. 54.
    Martinez, V. D., Vucic, E. A., Thu, K. L., Hubaux, R., Enfield, K. S., Pikor, L. A., et al. (2015). Unique somatic and malignant expression patterns implicate PIWI-interacting RNAs in cancer-type specific biology. Science Reports, 5, 10423. doi: 10.1038/srep10423.CrossRefGoogle Scholar
  55. 55.
    Ferreira, H. J., Heyn, H., Garcia del Muro, X., Vidal, A., Larriba, S., Munoz, C., et al. (2014). Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis. Epigenetics, 9(1), 113–118. doi: 10.4161/epi.27237.PubMedCrossRefGoogle Scholar
  56. 56.
    Tycowski, K. T., Shu, M. D., & Steitz, J. A. (1996). A mammalian gene with introns instead of exons generating stable RNA products. Nature, 379(6564), 464–466. doi: 10.1038/379464a0.PubMedCrossRefGoogle Scholar
  57. 57.
    Williams, G. T., & Farzaneh, F. (2012). Are snoRNAs and snoRNA host genes new players in cancer? Nature Reviews Cancer, 12(2), 84–88. doi: 10.1038/nrc3195.PubMedGoogle Scholar
  58. 58.
    Kiss-Laszlo, Z., Henry, Y., Bachellerie, J. P., Caizergues-Ferrer, M., & Kiss, T. (1996). Site-specific ribose methylation of preribosomal RNA: a novel function for small nucleolar RNAs. Cell, 85(7), 1077–1088.PubMedCrossRefGoogle Scholar
  59. 59.
    Decatur, W. A., & Fournier, M. J. (2002). rRNA modifications and ribosome function. Trends in Biochemical Sciences, 27(7), 344–351.PubMedCrossRefGoogle Scholar
  60. 60.
    Weinstein, L. B., & Steitz, J. A. (1999). Guided tours: from precursor snoRNA to functional snoRNP. Current Opinion in Cell Biology, 11(3), 378–384. doi: 10.1016/S0955-0674(99)80053-2.PubMedCrossRefGoogle Scholar
  61. 61.
    Ni, J., Tien, A. L., & Fournier, M. J. (1997). Small nucleolar RNAs direct site-specific synthesis of pseudouridine in ribosomal RNA. Cell, 89(4), 565–573.PubMedCrossRefGoogle Scholar
  62. 62.
    Darzacq, X., Jady, B. E., Verheggen, C., Kiss, A. M., Bertrand, E., & Kiss, T. (2002). Cajal body-specific small nuclear RNAs: a novel class of 2’-O-methylation and pseudouridylation guide RNAs. EMBO Journal, 21(11), 2746–2756. doi: 10.1093/emboj/21.11.2746.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Ono, M., Scott, M. S., Yamada, K., Avolio, F., Barton, G. J., & Lamond, A. I. (2011). Identification of human miRNA precursors that resemble box C/D snoRNAs. Nucleic Acids Research, 39(9), 3879–3891. doi: 10.1093/nar/gkq1355.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Brameier, M., Herwig, A., Reinhardt, R., Walter, L., & Gruber, J. (2011). Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs. Nucleic Acids Research, 39(2), 675–686. doi: 10.1093/nar/gkq776.PubMedCrossRefGoogle Scholar
  65. 65.
    Su, H., Xu, T., Ganapathy, S., Shadfan, M., Long, M., Huang, T. H., et al. (2014). Elevated snoRNA biogenesis is essential in breast cancer. Oncogene, 33(11), 1348–1358. doi: 10.1038/onc.2013.89.PubMedCrossRefGoogle Scholar
  66. 66.
    Morris, K. V., & Mattick, J. S. (2014). The rise of regulatory RNA. Nature Reviews Genetics, 15(6), 423–437. doi: 10.1038/nrg3722.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Goodarzi, H., Liu, X., Nguyen, H. C., Zhang, S., Fish, L., & Tavazoie, S. F. (2015). Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement. Cell, 161(4), 790–802. doi: 10.1016/j.cell.2015.02.053.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Gebetsberger, J., & Polacek, N. (2013). Slicing tRNAs to boost functional ncRNA diversity. RNA Biology, 10(12), 1798–1806. doi: 10.4161/rna.27177.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Taft, R. J., Hawkins, P. G., Mattick, J. S., & Morris, K. V. (2011). The relationship between transcription initiation RNAs and CCCTC-binding factor (CTCF) localization. Epigenetics & Chromatin, 4, 13. doi: 10.1186/1756-8935-4-13.CrossRefGoogle Scholar
  70. 70.
    Kowalczyk, M. S., Higgs, D. R., & Gingeras, T. R. (2012). Molecular biology: RNA discrimination. Nature, 482(7385), 310–311. doi: 10.1038/482310a.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhao, Z., Dammert, M. A., Grummt, I., & Bierhoff, H. (2016). lncRNA-induced nucleosome repositioning reinforces transcriptional repression of rRNA genes upon hypotonic stress. Cell Reports, 14(8), 1876–1882. doi: 10.1016/j.celrep.2016.01.073.PubMedCrossRefGoogle Scholar
  72. 72.
    Wang, D., Garcia-Bassets, I., Benner, C., Li, W., Su, X., Zhou, Y., et al. (2011). Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature, 474(7351), 390–394. doi: 10.1038/nature10006.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Wang, K. C., Yang, Y. W., Liu, B., Sanyal, A., Corces-Zimmerman, R., Chen, Y., et al. (2011). A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature, 472(7341), 120–124. doi: 10.1038/nature09819.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Nagano, T., Mitchell, J. A., Sanz, L. A., Pauler, F. M., Ferguson-Smith, A. C., Feil, R., et al. (2008). The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science, 322(5908), 1717–1720. doi: 10.1126/science.1163802.PubMedCrossRefGoogle Scholar
  75. 75.
    Maruyama, A., Mimura, J., & Itoh, K. (2014). Non-coding RNA derived from the region adjacent to the human HO-1 E2 enhancer selectively regulates HO-1 gene induction by modulating Pol II binding. Nucleic Acids Research, 42(22), 13599–13614. doi: 10.1093/nar/gku1169.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Li, W., Notani, D., Ma, Q., Tanasa, B., Nunez, E., Chen, A. Y., et al. (2013). Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature, 498(7455), 516–520. doi: 10.1038/nature12210.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Faghihi, M. A., Modarresi, F., Khalil, A. M., Wood, D. E., Sahagan, B. G., Morgan, T. E., et al. (2008). Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nature Medicine, 14(7), 723–730. doi: 10.1038/nm1784.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Yoon, J. H., Abdelmohsen, K., Srikantan, S., Yang, X., Martindale, J. L., De, S., et al. (2012). LincRNA-p21 suppresses target mRNA translation. Molecular Cell, 47(4), 648–655. doi: 10.1016/j.molcel.2012.06.027.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W. J., & Pandolfi, P. P. (2010). A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature, 465(7301), 1033–1038. doi: 10.1038/nature09144.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., et al. (2013). Natural RNA circles function as efficient microRNA sponges. Nature, 495(7441), 384–388. doi: 10.1038/nature11993.PubMedCrossRefGoogle Scholar
  81. 81.
    Hansen, T. B., Wiklund, E. D., Bramsen, J. B., Villadsen, S. B., Statham, A. L., Clark, S. J., et al. (2011). miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO Journal, 30(21), 4414–4422. doi: 10.1038/emboj.2011.359.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Fatica, A., & Bozzoni, I. (2014). Long non-coding RNAs: new players in cell differentiation and development. Nature Reviews Genetics, 15(1), 7–21. doi: 10.1038/nrg3606.PubMedCrossRefGoogle Scholar
  83. 83.
    Willingham, A. T., Orth, A. P., Batalov, S., Peters, E. C., Wen, B. G., Aza-Blanc, P., et al. (2005). A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science, 309(5740), 1570–1573. doi: 10.1126/science.1115901.PubMedCrossRefGoogle Scholar
  84. 84.
    Montes, M., Nielsen, M. M., Maglieri, G., Jacobsen, A., Hojfeldt, J., Agrawal-Singh, S., et al. (2015). The lncRNA MIR31HG regulates p16(INK4A) expression to modulate senescence. Nature Communications, 6, 6967. doi: 10.1038/ncomms7967.PubMedCrossRefGoogle Scholar
  85. 85.
    Pelechano, V., & Steinmetz, L. M. (2013). Gene regulation by antisense transcription. Nature Reviews Genetics, 14(12), 880–893. doi: 10.1038/nrg3594.PubMedCrossRefGoogle Scholar
  86. 86.
    Balbin, O. A., Malik, R., Dhanasekaran, S. M., Prensner, J. R., Cao, X., Wu, Y. M., et al. (2015). The landscape of antisense gene expression in human cancers. Genome Research, 25(7), 1068–1079. doi: 10.1101/gr.180596.114.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Lam, M. T., Li, W., Rosenfeld, M. G., & Glass, C. K. (2014). Enhancer RNAs and regulated transcriptional programs. Trends in Biochemical Sciences, 39(4), 170–182. doi: 10.1016/j.tibs.2014.02.007.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Heinz, S., Romanoski, C. E., Benner, C., & Glass, C. K. (2015). The selection and function of cell type-specific enhancers. Nature Reviews Molecular Cell Biology, 16(3), 144–154. doi: 10.1038/nrm3949.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Hsieh, C. L., Fei, T., Chen, Y., Li, T., Gao, Y., Wang, X., et al. (2014). Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proceedings of the National Academy of Sciences of the United States of America, 111(20), 7319–7324. doi: 10.1073/pnas.1324151111.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Korkmaz, G., Lopes, R., Ugalde, A. P., Nevedomskaya, E., Han, R., Myacheva, K., et al. (2016). Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9. Nature Biotechnology, 34(2), 192–198. doi: 10.1038/nbt.3450.PubMedCrossRefGoogle Scholar
  91. 91.
    Kalyana-Sundaram, S., Kumar-Sinha, C., Shankar, S., Robinson, D. R., Wu, Y. M., Cao, X., et al. (2012). Expressed pseudogenes in the transcriptional landscape of human cancers. Cell, 149(7), 1622–1634. doi: 10.1016/j.cell.2012.04.041.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Pei, B., Sisu, C., Frankish, A., Howald, C., Habegger, L., Mu, X. J., et al. (2012). The GENCODE pseudogene resource. Genome Biology, 13(9), R51. doi: 10.1186/gb-2012-13-9-r51.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Han, Y. J., Ma, S. F., Yourek, G., Park, Y. D., & Garcia, J. G. (2011). A transcribed pseudogene of MYLK promotes cell proliferation. FASEB Journal, 25(7), 2305–2312. doi: 10.1096/fj.10-177808.PubMedCrossRefGoogle Scholar
  94. 94.
    Watanabe, T., Totoki, Y., Toyoda, A., Kaneda, M., Kuramochi-Miyagawa, S., Obata, Y., et al. (2008). Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature, 453(7194), 539–543. doi: 10.1038/nature06908.PubMedCrossRefGoogle Scholar
  95. 95.
    Hawkins, P. G., & Morris, K. V. (2010). Transcriptional regulation of Oct4 by a long non-coding RNA antisense to Oct4-pseudogene 5. Transcription, 1(3), 165–175. doi: 10.4161/trns.1.3.13332.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Siegel, R., Naishadham, D., & Jemal, A. (2013). Cancer statistics, 2013. CA: A Cancer Journal for Clinicians, 63(1), 11–30. doi: 10.3322/caac.21166.Google Scholar
  97. 97.
    Bill-Axelson, A., Holmberg, L., Garmo, H., Rider, J. R., Taari, K., Busch, C., et al. (2014). Radical prostatectomy or watchful waiting in early prostate cancer. New England Journal of Medicine, 370(10), 932–942. doi: 10.1056/NEJMoa1311593.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Tomlins, S. A., Laxman, B., Dhanasekaran, S. M., Helgeson, B. E., Cao, X., Morris, D. S., et al. (2007). Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature, 448(7153), 595–599. doi: 10.1038/nature06024.PubMedCrossRefGoogle Scholar
  99. 99.
    Abd Elmageed, Z. Y., Yang, Y., Thomas, R., Ranjan, M., Mondal, D., Moroz, K., et al. (2014). Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells, 32(4), 983–997. doi: 10.1002/stem.1619.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Hudson, R. S., Yi, M., Esposito, D., Watkins, S. K., Hurwitz, A. A., Yfantis, H. G., et al. (2012). MicroRNA-1 is a candidate tumor suppressor and prognostic marker in human prostate cancer. Nucleic Acids Research, 40(8), 3689–3703. doi: 10.1093/nar/gkr1222.PubMedCrossRefGoogle Scholar
  101. 101.
    Lin, P. C., Chiu, Y. L., Banerjee, S., Park, K., Mosquera, J. M., Giannopoulou, E., et al. (2013). Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression. Cancer Research, 73(3), 1232–1244. doi: 10.1158/0008-5472.CAN-12-2968.PubMedCrossRefGoogle Scholar
  102. 102.
    Benassi, B., Flavin, R., Marchionni, L., Zanata, S., Pan, Y., Chowdhury, D., et al. (2012). MYC is activated by USP2a-mediated modulation of microRNAs in prostate cancer. Cancer Discovery, 2(3), 236–247. doi: 10.1158/2159-8290.CD-11-0219.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Majid, S., Dar, A. A., Saini, S., Shahryari, V., Arora, S., Zaman, M. S., et al. (2013). miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways. Clinical Cancer Research, 19(1), 73–84. doi: 10.1158/1078-0432.CCR-12-2952.PubMedCrossRefGoogle Scholar
  104. 104.
    Suh, S. O., Chen, Y., Zaman, M. S., Hirata, H., Yamamura, S., Shahryari, V., et al. (2011). MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. Carcinogenesis, 32(5), 772–778. doi: 10.1093/carcin/bgr036.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Hart, M., Wach, S., Nolte, E., Szczyrba, J., Menon, R., Taubert, H., et al. (2013). The proto-oncogene ERG is a target of microRNA miR-145 in prostate cancer. FEBS Journal, 280(9), 2105–2116. doi: 10.1111/febs.12236.PubMedCrossRefGoogle Scholar
  106. 106.
    Larne, O., Hagman, Z., Lilja, H., Bjartell, A., Edsjo, A., & Ceder, Y. (2015). miR-145 suppress the androgen receptor in prostate cancer cells and correlates to prostate cancer prognosis. Carcinogenesis, 36(8), 858–866. doi: 10.1093/carcin/bgv063.PubMedCrossRefGoogle Scholar
  107. 107.
    Wang, C., Tao, W., Ni, S., Chen, Q., Zhao, Z., Ma, L., et al. (2015). Tumor-suppressive microRNA-145 induces growth arrest by targeting SENP1 in human prostate cancer cells. Cancer Science, 106(4), 375–382. doi: 10.1111/cas.12626.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Kaukoniemi, K. M., Rauhala, H. E., Scaravilli, M., Latonen, L., Annala, M., Vessella, R. L., et al. (2015). Epigenetically altered miR-193b targets cyclin D1 in prostate cancer. Cancer Medicine, 4(9), 1417–1425. doi: 10.1002/cam4.486.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Rauhala, H. E., Jalava, S. E., Isotalo, J., Bracken, H., Lehmusvaara, S., Tammela, T. L., et al. (2010). miR-193b is an epigenetically regulated putative tumor suppressor in prostate cancer. International Journal of Cancer, 127(6), 1363–1372. doi: 10.1002/ijc.25162.PubMedCrossRefGoogle Scholar
  110. 110.
    Xie, C., Jiang, X. H., Zhang, J. T., Sun, T. T., Dong, J. D., Sanders, A. J., et al. (2013). CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer. Oncogene, 32(18), 2282–2291, 2291 e2281-2287, doi:10.1038/onc.2012.251.Google Scholar
  111. 111.
    Saini, S., Majid, S., Yamamura, S., Tabatabai, L., Suh, S. O., Shahryari, V., et al. (2011). Regulatory role of mir-203 in prostate cancer progression and metastasis. Clinical Cancer Research, 17(16), 5287–5298. doi: 10.1158/1078-0432.CCR-10-2619.PubMedCrossRefGoogle Scholar
  112. 112.
    Viticchie, G., Lena, A. M., Latina, A., Formosa, A., Gregersen, L. H., Lund, A. H., et al. (2011). MiR-203 controls proliferation, migration and invasive potential of prostate cancer cell lines. Cell Cycle, 10(7), 1121–1131.PubMedCrossRefGoogle Scholar
  113. 113.
    Hailer, A., Grunewald, T. G., Orth, M., Reiss, C., Kneitz, B., Spahn, M., et al. (2014). Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration. Oncotarget, 5(12), 4144–4153. doi: 10.18632/oncotarget.1928.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Xiang, J., Bian, C., Wang, H., Huang, S., & Wu, D. (2015). MiR-203 down-regulates Rap1A and suppresses cell proliferation, adhesion and invasion in prostate cancer. Journal of Experimental & Clinical Cancer Research, 34, 8. doi: 10.1186/s13046-015-0125-x.CrossRefGoogle Scholar
  115. 115.
    Siu, M. K., Abou-Kheir, W., Yin, J. J., Chang, Y. S., Barrett, B., Suau, F., et al. (2014). Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance. Oncotarget, 5(11), 3770–3784. doi: 10.18632/oncotarget.1994.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Hulf, T., Sibbritt, T., Wiklund, E. D., Patterson, K., Song, J. Z., Stirzaker, C., et al. (2013). Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer. Oncogene, 32(23), 2891–2899. doi: 10.1038/onc.2012.300.PubMedCrossRefGoogle Scholar
  117. 117.
    Gandellini, P., Folini, M., Longoni, N., Pennati, M., Binda, M., Colecchia, M., et al. (2009). miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Research, 69(6), 2287–2295. doi: 10.1158/0008-5472.CAN-08-2894.PubMedCrossRefGoogle Scholar
  118. 118.
    Hagman, Z., Haflidadottir, B. S., Ceder, J. A., Larne, O., Bjartell, A., Lilja, H., et al. (2013). miR-205 negatively regulates the androgen receptor and is associated with adverse outcome of prostate cancer patients. British Journal of Cancer, 108(8), 1668–1676. doi: 10.1038/bjc.2013.131.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Tucci, P., Agostini, M., Grespi, F., Markert, E. K., Terrinoni, A., Vousden, K. H., et al. (2012). Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 109(38), 15312–15317. doi: 10.1073/pnas.1110977109.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Lin, Z. Y., Huang, Y. Q., Zhang, Y. Q., Han, Z. D., He, H. C., Ling, X. H., et al. (2014). MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1. International Journal of Cancer, 135(3), 541–550. doi: 10.1002/ijc.28707.PubMedCrossRefGoogle Scholar
  121. 121.
    Goto, Y., Nishikawa, R., Kojima, S., Chiyomaru, T., Enokida, H., Inoguchi, S., et al. (2014). Tumour-suppressive microRNA-224 inhibits cancer cell migration and invasion via targeting oncogenic TPD52 in prostate cancer. FEBS Letters, 588(10), 1973–1982. doi: 10.1016/j.febslet.2014.04.020.PubMedCrossRefGoogle Scholar
  122. 122.
    Ribas, J., Ni, X., Haffner, M., Wentzel, E. A., Salmasi, A. H., Chowdhury, W. H., et al. (2009). miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Research, 69(18), 7165–7169. doi: 10.1158/0008-5472.CAN-09-1448.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Coppola, V., Musumeci, M., Patrizii, M., Cannistraci, A., Addario, A., Maugeri-Sacca, M., et al. (2013). BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial-mesenchymal transition. Oncogene, 32(14), 1843–1853. doi: 10.1038/onc.2012.194.PubMedCrossRefGoogle Scholar
  124. 124.
    Yang, C. H., Pfeffer, S. R., Sims, M., Yue, J., Wang, Y., Linga, V. G., et al. (2015). The oncogenic microRNA-21 inhibits the tumor suppressive activity of FBXO11 to promote tumorigenesis. Journal of Biological Chemistry, 290(10), 6037–6046. doi: 10.1074/jbc.M114.632125.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Jalava, S. E., Urbanucci, A., Latonen, L., Waltering, K. K., Sahu, B., Janne, O. A., et al. (2012). Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer. Oncogene, 31(41), 4460–4471. doi: 10.1038/onc.2011.624.PubMedCrossRefGoogle Scholar
  126. 126.
    Liao, H., Xiao, Y., Hu, Y., Xiao, Y., Yin, Z., & Liu, L. (2015). microRNA-32 induces radioresistance by targeting DAB2IP and regulating autophagy in prostate cancer cells. Oncology Letters, 10(4), 2055–2062. doi: 10.3892/ol.2015.3551.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Ma, Y., Yang, H. Z., Dong, B. J., Zou, H. B., Zhou, Y., Kong, X. M., et al. (2014). Biphasic regulation of autophagy by miR-96 in prostate cancer cells under hypoxia. Oncotarget, 5(19), 9169–9182. doi: 10.18632/oncotarget.2396.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Haflidadottir, B. S., Larne, O., Martin, M., Persson, M., Edsjo, A., Bjartell, A., et al. (2013). Upregulation of miR-96 enhances cellular proliferation of prostate cancer cells through FOXO1. PLoS ONE, 8(8), e72400. doi: 10.1371/journal.pone.0072400.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Siu, M. K., Tsai, Y. C., Chang, Y. S., Yin, J. J., Suau, F., Chen, W. Y., et al. (2015). Transforming growth factor-beta promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway. Oncogene, 34(36), 4767–4776. doi: 10.1038/onc.2014.414.PubMedCrossRefGoogle Scholar
  130. 130.
    Mihelich, B. L., Khramtsova, E. A., Arva, N., Vaishnav, A., Johnson, D. N., Giangreco, A. A., et al. (2011). miR-183-96-182 cluster is overexpressed in prostate tissue and regulates zinc homeostasis in prostate cells. Journal of Biological Chemistry, 286(52), 44503–44511. doi: 10.1074/jbc.M111.262915.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Ueno, K., Hirata, H., Shahryari, V., Deng, G., Tanaka, Y., Tabatabai, Z. L., et al. (2013). microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer. British Journal of Cancer, 108(8), 1659–1667. doi: 10.1038/bjc.2013.125.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Larne, O., Ostling, P., Haflidadottir, B. S., Hagman, Z., Aakula, A., Kohonen, P., et al. (2015). miR-183 in prostate cancer cells positively regulates synthesis and serum levels of prostate-specific antigen. European Urology, 68(4), 581–588. doi: 10.1016/j.eururo.2014.12.025.PubMedCrossRefGoogle Scholar
  133. 133.
    Costa-Pinheiro, P., Ramalho-Carvalho, J., Vieira, F. Q., Torres-Ferreira, J., Oliveira, J., Goncalves, C. S., et al. (2015). MicroRNA-375 plays a dual role in prostate carcinogenesis. Clinical Epigenetics, 7(1), 42. doi: 10.1186/s13148-015-0076-2.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Szczyrba, J., Nolte, E., Wach, S., Kremmer, E., Stohr, R., Hartmann, A., et al. (2011). Downregulation of Sec23A protein by miRNA-375 in prostate carcinoma. Molecular Cancer Research, 9(6), 791–800. doi: 10.1158/1541-7786.MCR-10-0573.PubMedCrossRefGoogle Scholar
  135. 135.
    Dong, X. Y., Rodriguez, C., Guo, P., Sun, X., Talbot, J. T., Zhou, W., et al. (2008). SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer. Human Molecular Genetics, 17(7), 1031–1042. doi: 10.1093/hmg/ddm375.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Sieron, P., Hader, C., Hatina, J., Engers, R., Wlazlinski, A., Muller, M., et al. (2009). DKC1 overexpression associated with prostate cancer progression. British Journal of Cancer, 101(8), 1410–1416. doi: 10.1038/sj.bjc.6605299.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Thomson, E., Ferreira-Cerca, S., & Hurt, E. (2013). Eukaryotic ribosome biogenesis at a glance. Journal of Cell Science, 126(Pt 21), 4815–4821. doi: 10.1242/jcs.111948.PubMedCrossRefGoogle Scholar
  138. 138.
    Martens-Uzunova, E. S., Hoogstrate, Y., Kalsbeek, A., Pigmans, B., Vredenbregt-van den Berg, M., Dits, N., et al. (2015). C/D-box snoRNA-derived RNA production is associated with malignant transformation and metastatic progression in prostate cancer. Oncotarget, 6(19), 17430–17444.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Uemura, M., Zheng, Q., Koh, C. M., Nelson, W. G., Yegnasubramanian, S., & De Marzo, A. M. (2012). Overexpression of ribosomal RNA in prostate cancer is common but not linked to rDNA promoter hypomethylation. Oncogene, 31(10), 1254–1263. doi: 10.1038/onc.2011.319.PubMedCrossRefGoogle Scholar
  140. 140.
    McStay, B., & Grummt, I. (2008). The epigenetics of rRNA genes: from molecular to chromosome biology. Annual Review of Cell and Developmental Biology, 24, 131–157. doi: 10.1146/annurev.cellbio.24.110707.175259.PubMedCrossRefGoogle Scholar
  141. 141.
    Li, S., Hu, M. G., Sun, Y., Yoshioka, N., Ibaragi, S., Sheng, J., et al. (2013). Angiogenin mediates androgen-stimulated prostate cancer growth and enables castration resistance. Molecular Cancer Research, 11(10), 1203–1214. doi: 10.1158/1541-7786.MCR-13-0072.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Koh, C. M., Gurel, B., Sutcliffe, S., Aryee, M. J., Schultz, D., Iwata, T., et al. (2011). Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene. American Journal of Pathology, 178(4), 1824–1834. doi: 10.1016/j.ajpath.2010.12.040.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Lee, Y. S., Shibata, Y., Malhotra, A., & Dutta, A. (2009). A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). Genes and Development, 23(22), 2639–2649. doi: 10.1101/gad.1837609.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Olvedy, M., Scaravilli, M., Hoogstrate, Y., Visakorpi, T., Jenster, G., & Martens-Uzunova, E. (2016). A comprehensive repertoire of tRNA-derived fragments in prostate cancer. Oncotarget. doi: 10.18632/oncotarget.8293.PubMedGoogle Scholar
  145. 145.
    Honda, S., Loher, P., Shigematsu, M., Palazzo, J. P., Suzuki, R., Imoto, I., et al. (2015). Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers. Proceedings of the National Academy of Sciences of the United States of America, 112(29), E3816–3825. doi: 10.1073/pnas.1510077112.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Ivanov, P., Emara, M. M., Villen, J., Gygi, S. P., & Anderson, P. (2011). Angiogenin-induced tRNA fragments inhibit translation initiation. Molecular Cell, 43(4), 613–623. doi: 10.1016/j.molcel.2011.06.022.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Maute, R. L., Schneider, C., Sumazin, P., Holmes, A., Califano, A., Basso, K., et al. (2013). tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America, 110(4), 1404–1409. doi: 10.1073/pnas.1206761110.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Siomi, M. C., Sato, K., Pezic, D., & Aravin, A. A. (2011). PIWI-interacting small RNAs: the vanguard of genome defence. Nature Reviews Molecular Cell Biology, 12(4), 246–258. doi: 10.1038/nrm3089.PubMedCrossRefGoogle Scholar
  149. 149.
    Boormans, J. L., Korsten, H., Ziel-van der Made, A. J., van Leenders, G. J., de Vos, C. V., Jenster, G., et al. (2013). Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer. International Journal of Cancer, 133(2), 335–345. doi: 10.1002/ijc.28025.PubMedCrossRefGoogle Scholar
  150. 150.
    Yang, Y., Zhang, X., Song, D., & Wei, J. (2015). Piwil2 modulates the invasion and metastasis of prostate cancer by regulating the expression of matrix metalloproteinase-9 and epithelial-mesenchymal transitions. Oncology Letters, 10(3), 1735–1740. doi: 10.3892/ol.2015.3392.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Luo, G., Wang, M., Wu, X., Tao, D., Xiao, X., Wang, L., et al. (2015). Long non-coding RNA MEG3 inhibits cell proliferation and induces apoptosis in prostate cancer. Cellular Physiology and Biochemistry, 37(6), 2209–2220. doi: 10.1159/000438577.PubMedCrossRefGoogle Scholar
  152. 152.
    Malik, R., Patel, L., Prensner, J. R., Shi, Y., Iyer, M. K., Subramaniyan, S., et al. (2014). The lncRNA PCAT29 inhibits oncogenic phenotypes in prostate cancer. Molecular Cancer Research, 12(8), 1081–1087. doi: 10.1158/1541-7786.MCR-14-0257.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Kawamura, N., Nimura, K., Nagano, H., Yamaguchi, S., Nonomura, N., & Kaneda, Y. (2015). CRISPR/Cas9-mediated gene knockout of NANOG and NANOGP8 decreases the malignant potential of prostate cancer cells. Oncotarget, 6(26), 22361–22374. doi: 10.18632/oncotarget.4293.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Sakurai, K., Reon, B. J., Anaya, J., & Dutta, A. (2015). The lncRNA DRAIC/PCAT29 locus constitutes a tumor-suppressive nexus. Molecular Cancer Research, 13(5), 828–838. doi: 10.1158/1541-7786.MCR-15-0016-T.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Pickard, M. R., Mourtada-Maarabouni, M., & Williams, G. T. (2013). Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. Biochimica et Biophysica Acta, 1832(10), 1613–1623. doi: 10.1016/j.bbadis.2013.05.005.PubMedCrossRefGoogle Scholar
  156. 156.
    Hung, C. L., Wang, L. Y., Yu, Y. L., Chen, H. W., Srivastava, S., Petrovics, G., et al. (2014). A long noncoding RNA connects c-Myc to tumor metabolism. Proceedings of the National Academy of Sciences of the United States of America, 111(52), 18697–18702. doi: 10.1073/pnas.1415669112.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Yang, L., Lin, C., Jin, C., Yang, J. C., Tanasa, B., Li, W., et al. (2013). lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature, 500(7464), 598–602. doi: 10.1038/nature12451.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Cui, Z., Ren, S., Lu, J., Wang, F., Xu, W., Sun, Y., et al. (2013). The prostate cancer-up-regulated long noncoding RNA PlncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor. Urologic Oncology, 31(7), 1117–1123. doi: 10.1016/j.urolonc.2011.11.030.PubMedCrossRefGoogle Scholar
  159. 159.
    Zhang, A., Zhao, J. C., Kim, J., Fong, K. W., Yang, Y. A., Chakravarti, D., et al. (2015). LncRNA HOTAIR enhances the androgen-receptor-mediated transcriptional program and drives castration-resistant prostate cancer. Cell Reports, 13(1), 209–221. doi: 10.1016/j.celrep.2015.08.069.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Ylipaa, A., Kivinummi, K., Kohvakka, A., Annala, M., Latonen, L., Scaravilli, M., et al. (2015). Transcriptome sequencing reveals PCAT5 as a novel ERG-regulated long noncoding RNA in prostate cancer. Cancer Research, 75(19), 4026–4031. doi: 10.1158/0008-5472.CAN-15-0217.PubMedCrossRefGoogle Scholar
  161. 161.
    Orfanelli, U., Jachetti, E., Chiacchiera, F., Grioni, M., Brambilla, P., Briganti, A., et al. (2015). Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer. Oncogene, 34(16), 2094–2102. doi: 10.1038/onc.2014.144.PubMedCrossRefGoogle Scholar
  162. 162.
    Yap, K. L., Li, S., Munoz-Cabello, A. M., Raguz, S., Zeng, L., Mujtaba, S., et al. (2010). Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Molecular Cell, 38(5), 662–674. doi: 10.1016/j.molcel.2010.03.021.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Takayama, K., Horie-Inoue, K., Katayama, S., Suzuki, T., Tsutsumi, S., Ikeda, K., et al. (2013). Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO Journal, 32(12), 1665–1680. doi: 10.1038/emboj.2013.99.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Beckedorff, F. C., Ayupe, A. C., Crocci-Souza, R., Amaral, M. S., Nakaya, H. I., Soltys, D. T., et al. (2013). The intronic long noncoding RNA ANRASSF1 recruits PRC2 to the RASSF1A promoter, reducing the expression of RASSF1A and increasing cell proliferation. PLoS Genetics, 9(8), e1003705. doi: 10.1371/journal.pgen.1003705.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Loven, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., et al. (2013). Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell, 153(2), 320–334. doi: 10.1016/j.cell.2013.03.036.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Puc, J., Kozbial, P., Li, W., Tan, Y., Liu, Z., Suter, T., et al. (2015). Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell, 160(3), 367–380. doi: 10.1016/j.cell.2014.12.023.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Jin, C., Yang, L., Xie, M., Lin, C., Merkurjev, D., Yang, J. C., et al. (2014). Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens. Proceedings of the National Academy of Sciences of the United States of America, 111(25), 9235–9240. doi: 10.1073/pnas.1404303111.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Tripathi, V., Ellis, J. D., Shen, Z., Song, D. Y., Pan, Q., Watt, A. T., et al. (2010). The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Molecular Cell, 39(6), 925–938. doi: 10.1016/j.molcel.2010.08.011.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Wilusz, J. E., Freier, S. M., & Spector, D. L. (2008). 3’ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell, 135(5), 919–932. doi: 10.1016/j.cell.2008.10.012.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Clemson, C. M., Hutchinson, J. N., Sara, S. A., Ensminger, A. W., Fox, A. H., Chess, A., et al. (2009). An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Molecular Cell, 33(6), 717–726. doi: 10.1016/j.molcel.2009.01.026.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Wang, D., Ding, L., Wang, L., Zhao, Y., Sun, Z., Karnes, R. J., et al. (2015). LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer. Oncotarget, 6(38), 41045–41055. doi: 10.18632/oncotarget.5728.PubMedPubMedCentralGoogle Scholar
  172. 172.
    Chakravarty, D., Sboner, A., Nair, S. S., Giannopoulou, E., Li, R., Hennig, S., et al. (2014). The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nature Communications, 5, 5383. doi: 10.1038/ncomms6383.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Ren, S., Liu, Y., Xu, W., Sun, Y., Lu, J., Wang, F., et al. (2013). Long noncoding RNA MALAT-1 is a new potential therapeutic target for castration resistant prostate cancer. Journal of Urology, 190(6), 2278–2287. doi: 10.1016/j.juro.2013.07.001.PubMedCrossRefGoogle Scholar
  174. 174.
    Prensner, J. R., Iyer, M. K., Balbin, O. A., Dhanasekaran, S. M., Cao, Q., Brenner, J. C., et al. (2011). Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nature Biotechnology, 29(8), 742–749. doi: 10.1038/nbt.1914.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Prensner, J. R., Chen, W., Iyer, M. K., Cao, Q., Ma, T., Han, S., et al. (2014). PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Research, 74(6), 1651–1660. doi: 10.1158/0008-5472.CAN-13-3159.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Prensner, J. R., Chen, W., Han, S., Iyer, M. K., Cao, Q., Kothari, V., et al. (2014). The long non-coding RNA PCAT-1 promotes prostate cancer cell proliferation through cMyc. Neoplasia, 16(11), 900–908. doi: 10.1016/j.neo.2014.09.001.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Prensner, J. R., Iyer, M. K., Sahu, A., Asangani, I. A., Cao, Q., Patel, L., et al. (2013). The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nature Genetics, 45(11), 1392–1398. doi: 10.1038/ng.2771.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Salameh, A., Lee, A. K., Cardo-Vila, M., Nunes, D. N., Efstathiou, E., Staquicini, F. I., et al. (2015). PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3. Proceedings of the National Academy of Sciences of the United States of America, 112(27), 8403–8408. doi: 10.1073/pnas.1507882112.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Hudson, R. S., Yi, M., Volfovsky, N., Prueitt, R. L., Esposito, D., Volinia, S., et al. (2013). Transcription signatures encoded by ultraconserved genomic regions in human prostate cancer. Molecular Cancer, 12, 13. doi: 10.1186/1476-4598-12-13.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Calin, G. A., Liu, C. G., Ferracin, M., Hyslop, T., Spizzo, R., Sevignani, C., et al. (2007). Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell, 12(3), 215–229. doi: 10.1016/j.ccr.2007.07.027.PubMedCrossRefGoogle Scholar
  181. 181.
    Mestdagh, P., Fredlund, E., Pattyn, F., Rihani, A., Van Maerken, T., Vermeulen, J., et al. (2010). An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours. Oncogene, 29(24), 3583–3592. doi: 10.1038/onc.2010.106.PubMedCrossRefGoogle Scholar
  182. 182.
    Lujambio, A., Portela, A., Liz, J., Melo, S. A., Rossi, S., Spizzo, R., et al. (2010). CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Oncogene, 29(48), 6390–6401. doi: 10.1038/onc.2010.361.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Bao, B. Y., Lin, V. C., Yu, C. C., Yin, H. L., Chang, T. Y., Lu, T. L., et al. (2016). Genetic variants in ultraconserved regions associate with prostate cancer recurrence and survival. Science Reports, 6, 22124. doi: 10.1038/srep22124.CrossRefGoogle Scholar
  184. 184.
    Hessels, D., & Schalken, J. A. (2009). The use of PCA3 in the diagnosis of prostate cancer. Nature Reviews. Urology, 6(5), 255–261. doi: 10.1038/nrurol.2009.40.PubMedCrossRefGoogle Scholar
  185. 185.
    Mitchell, P. S., Parkin, R. K., Kroh, E. M., Fritz, B. R., Wyman, S. K., Pogosova-Agadjanyan, E. L., et al. (2008). Circulating microRNAs as stable blood-based markers for cancer detection. Proceedings of the National Academy of Sciences of the United States of America, 105(30), 10513–10518. doi: 10.1073/pnas.0804549105.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Nguyen, H. C., Xie, W., Yang, M., Hsieh, C. L., Drouin, S., Lee, G. S., et al. (2013). Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer. Prostate, 73(4), 346–354. doi: 10.1002/pros.22572.PubMedCrossRefGoogle Scholar
  187. 187.
    Zhang, H. L., Yang, L. F., Zhu, Y., Yao, X. D., Zhang, S. L., Dai, B., et al. (2011). Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy. Prostate, 71(3), 326–331. doi: 10.1002/pros.21246.PubMedCrossRefGoogle Scholar
  188. 188.
    Kristensen, H., Haldrup, C., Strand, S., Mundbjerg, K., Mortensen, M. M., Thorsen, K., et al. (2014). Hypermethylation of the GABRE ~ miR-452 ~ miR-224 promoter in prostate cancer predicts biochemical recurrence after radical prostatectomy. Clinical Cancer Research, 20(8), 2169–2181. doi: 10.1158/1078-0432.CCR-13-2642.PubMedCrossRefGoogle Scholar
  189. 189.
    Bussemakers, M. J., van Bokhoven, A., Verhaegh, G. W., Smit, F. P., Karthaus, H. F., Schalken, J. A., et al. (1999). DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Research, 59(23), 5975–5979.PubMedGoogle Scholar
  190. 190.
    Auprich, M., Chun, F. K., Ward, J. F., Pummer, K., Babaian, R., Augustin, H., et al. (2011). Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging. European Urology, 59(1), 96–105. doi: 10.1016/j.eururo.2010.10.024.PubMedCrossRefGoogle Scholar
  191. 191.
    Leyten, G. H., Hessels, D., Jannink, S. A., Smit, F. P., de Jong, H., Cornel, E. B., et al. (2014). Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. European Urology, 65(3), 534–542. doi: 10.1016/j.eururo.2012.11.014.PubMedCrossRefGoogle Scholar
  192. 192.
    Lin, D. W., Newcomb, L. F., Brown, E. C., Brooks, J. D., Carroll, P. R., Feng, Z., et al. (2013). Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study. Clinical Cancer Research, 19(9), 2442–2450. doi: 10.1158/1078-0432.CCR-12-3283.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Huang, X., Yuan, T., Liang, M., Du, M., Xia, S., Dittmar, R., et al. (2015). Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. European Urology, 67(1), 33–41. doi: 10.1016/j.eururo.2014.07.035.PubMedCrossRefGoogle Scholar
  194. 194.
    Isin, M., Uysaler, E., Ozgur, E., Koseoglu, H., Sanli, O., Yucel, O. B., et al. (2015). Exosomal lncRNA-p21 levels may help to distinguish prostate cancer from benign disease. Frontiers in Genetics, 6, 168. doi: 10.3389/fgene.2015.00168.PubMedPubMedCentralGoogle Scholar
  195. 195.
    Hindorff, L. A., Sethupathy, P., Junkins, H. A., Ramos, E. M., Mehta, J. P., Collins, F. S., et al. (2009). Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of the United States of America, 106(23), 9362–9367. doi: 10.1073/pnas.0903103106.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Glinskii, A. B., Ma, S., Ma, J., Grant, D., Lim, C. U., Guest, I., et al. (2011). Networks of intergenic long-range enhancers and snpRNAs drive castration-resistant phenotype of prostate cancer and contribute to pathogenesis of multiple common human disorders. Cell Cycle, 10(20), 3571–3597. doi: 10.4161/cc.10.20.17842.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Jin, G., Sun, J., Isaacs, S. D., Wiley, K. E., Kim, S. T., Chu, L. W., et al. (2011). Human polymorphisms at long non-coding RNAs (lncRNAs) and association with prostate cancer risk. Carcinogenesis, 32(11), 1655–1659. doi: 10.1093/carcin/bgr187.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Al Olama, A. A., Kote-Jarai, Z., Giles, G. G., Guy, M., Morrison, J., Severi, G., et al. (2009). Multiple loci on 8q24 associated with prostate cancer susceptibility. Nature Genetics, 41(10), 1058–1060. doi: 10.1038/ng.452.PubMedCrossRefGoogle Scholar
  199. 199.
    Meyer, K. B., Maia, A. T., O’Reilly, M., Ghoussaini, M., Prathalingam, R., Porter-Gill, P., et al. (2011). A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression. PLoS Genetics, 7(7), e1002165. doi: 10.1371/journal.pgen.1002165.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    He, C. (2010). Grand challenge commentary: RNA epigenetics? Nature Chemical Biology, 6(12), 863–865. doi: 10.1038/nchembio.482.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • João Ramalho-Carvalho
    • 1
    • 2
  • Bastian Fromm
    • 3
  • Rui Henrique
    • 1
    • 4
    • 5
  • Carmen Jerónimo
    • 1
    • 5
    • 6
  1. 1.Cancer Biology & Epigenetics Group – Research CenterPortuguese Oncology Institute of Porto (CI-IPOP)PortoPortugal
  2. 2.Biomedical Sciences Graduate ProgramInstitute of Biomedical Sciences Abel Salazar–University of Porto (ICBAS-UP)PortoPortugal
  3. 3.Department of Tumor BiologyInstitute for Cancer Research, The Norwegian Radium Hospital, Oslo University HospitalOsloNorway
  4. 4.Departments of PathologyPortuguese Oncology Institute of PortoPortoPortugal
  5. 5.Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel SalazarUniversity of Porto (ICBAS-UP)PortoPortugal
  6. 6.Portuguese Oncology Institute of Porto, Research Center-LAB 3PortoPortugal

Personalised recommendations