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Non-coding RNAs, epigenetics, and cancer: tying it all together

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Abstract

While only a small part of the human genome encodes for proteins, biological functions for the so-called junk genome are increasingly being recognized through high-throughput technologies and mechanistic experimental studies. Indeed, novel mechanisms of gene regulation are being discovered that require coordinated interaction between DNA, RNA, and proteins. Therefore, interdisciplinary efforts are still needed to decipher these complex transcriptional networks. In this review, we discuss how non-coding RNAs (ncRNAs) are epigenetically regulated in cancer and metastases and consequently how ncRNAs participate in the sculpting of the epigenetic profile of a cancer cell, thus modulating the expression of other RNA molecules. In the latter case, ncRNAs not only affect the DNA methylation status of certain genomic loci but also interact with histone-modifying complexes, changing the structure of the chromatin itself. We present several examples of epigenetic changes causing aberrant expression of ncRNAs in the context of tumor progression. Interestingly, there are also important epigenetic changes and transcriptional regulatory effects derived from their aberrant expression. As ncRNAs can also be used as biomarkers for diagnosis and prognosis or explored as potential targets, we present insights into the use of ncRNAs for targeted cancer therapy.

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References

  1. Crick, F. H. (1958). On protein synthesis. Symposia of the Society for Experimental Biology, 12, 138–163.

    CAS  PubMed  Google Scholar 

  2. Alexander, R. P., Fang, G., Rozowsky, J., Snyder, M., & Gerstein, M. B. (2010). Annotating non-coding regions of the genome. Nature Reviews. Genetics, 11(8), 559–571.

    Article  CAS  PubMed  Google Scholar 

  3. Taft, R. J., Pheasant, M., & Mattick, J. S. (2007). The relationship between non-protein-coding DNA and eukaryotic complexity. BioEssays, 29(3), 288–299.

    Article  CAS  PubMed  Google Scholar 

  4. ENCODE. (2012). Project Consortium, an integrated encyclopedia of DNA elements in the human genome. Nature, 489(7414), 57–74.

    Article  CAS  Google Scholar 

  5. Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., Tanzer, A., Lagarde, J., Lin, W., Schlesinger, F., Xue, C., Marinov, G. K., Khatun, J., Williams, B. A., Zaleski, C., Rozowsky, J., Roder, M., Kokocinski, F., Abdelhamid, R. F., Alioto, T., Antoshechkin, I., Baer, M. T., Bar, N. S., Batut, P., Bell, K., Bell, I., Chakrabortty, S., Chen, X., Chrast, J., Curado, J., Derrien, T., Drenkow, J., Dumais, E., Dumais, J., Duttagupta, R., Falconnet, E., Fastuca, M., Fejes-Toth, K., Ferreira, P., Foissac, S., Fullwood, M. J., Gao, H., Gonzalez, D., Gordon, A., Gunawardena, H., Howald, C., Jha, S., Johnson, R., Kapranov, P., King, B., Kingswood, C., Luo, O. J., Park, E., Persaud, K., Preall, J. B., Ribeca, P., Risk, B., Robyr, D., Sammeth, M., Schaffer, L., See, L. H., Shahab, A., Skancke, J., Suzuki, A. M., Takahashi, H., Tilgner, H., Trout, D., Walters, N., Wang, H., Wrobel, J., Yu, Y., Ruan, X., Hayashizaki, Y., Harrow, J., Gerstein, M., Hubbard, T., Reymond, A., Antonarakis, S. E., Hannon, G., Giddings, M. C., Ruan, Y., Wold, B., Carninci, P., Guigo, R., & Gingeras, T. R. (2012). Landscape of transcription in human cells. Nature, 489(7414), 101–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dhanasekaran, K., Kumari, S., & Kanduri, C. (2013). Noncoding RNAs in chromatin organization and transcription regulation: an epigenetic view. Sub-Cellular Biochemistry, 61, 343–372.

    Article  CAS  PubMed  Google Scholar 

  7. Tay, Y., Kats, L., Salmena, L., Weiss, D., Tan, S. M., Ala, U., Karreth, F., Poliseno, L., Provero, P., Di Cunto, F., Lieberman, J., Rigoutsos, I., & Pandolfi, P. P. (2011). Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell, 147(2), 344–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kapranov, P., Cheng, J., Dike, S., Nix, D. A., Duttagupta, R., Willingham, A. T., Stadler, P. F., Hertel, J., Hackermuller, J., Hofacker, I. L., Bell, I., Cheung, E., Drenkow, J., Dumais, E., Patel, S., Helt, G., Ganesh, M., Ghosh, S., Piccolboni, A., Sementchenko, V., Tammana, H., & Gingeras, T. R. (2007). RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science, 316(5830), 1484–1488.

    Article  CAS  PubMed  Google Scholar 

  9. Walsh, C. P., Chaillet, J. R., & Bestor, T. H. (1998). Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nature Genetics, 20(2), 116–117.

    Article  CAS  PubMed  Google Scholar 

  10. Liang, G., Chan, M. F., Tomigahara, Y., Tsai, Y. C., Gonzales, F. A., Li, E., Laird, P. W., & Jones, P. A. (2002). Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Molecular and Cellular Biology, 22(2), 480–491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Slotkin, R. K., & Martienssen, R. (2007). Transposable elements and the epigenetic regulation of the genome. Nature Reviews. Genetics, 8(4), 272–285.

    Article  CAS  PubMed  Google Scholar 

  12. Xie, M., Hong, C., Zhang, B., Lowdon, R. F., Xing, X., Li, D., Zhou, X., Lee, H. J., Maire, C. L., Ligon, K. L., Gascard, P., Sigaroudinia, M., Tlsty, T. D., Kadlecek, T., Weiss, A., O'Geen, H., Farnham, P. J., Madden, P. A., Mungall, A. J., Tam, A., Kamoh, B., Cho, S., Moore, R., Hirst, M., Marra, M. A., Costello, J. F., & Wang, T. (2013). DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape. Nature Genetics, 45(7), 836–841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Reik, W., & Lewis, A. (2005). Co-evolution of X-chromosome inactivation and imprinting in mammals. Nature Reviews. Genetics, 6(5), 403–410.

    Article  CAS  PubMed  Google Scholar 

  14. Paulsen, M., & Ferguson-Smith, A. C. (2001). DNA methylation in genomic imprinting, development, and disease. The Journal of Pathology, 195(1), 97–110.

    Article  CAS  PubMed  Google Scholar 

  15. Li, E., Beard, C., & Jaenisch, R. (1993). Role for DNA methylation in genomic imprinting. Nature, 366(6453), 362–365.

    Article  CAS  PubMed  Google Scholar 

  16. Du, M., Zhou, W., Beatty, L. G., Weksberg, R., & Sadowski, P. D. (2004). The KCNQ1OT1 promoter, a key regulator of genomic imprinting in human chromosome 11p15.5. Genomics, 84(2), 288–300.

    Article  CAS  PubMed  Google Scholar 

  17. Peschansky, V. J., & Wahlestedt, C. (2014). Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics, 9(1), 3–12.

    Article  CAS  PubMed  Google Scholar 

  18. Morris, K. V., & Mattick, J. S. (2014). The rise of regulatory RNA. Nature Reviews. Genetics, 15(6), 423–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Morris, K. V., Chan, S. W., Jacobsen, S. E., & Looney, D. J. (2004). Small interfering RNA-induced transcriptional gene silencing in human cells. Science, 305(5688), 1289–1292.

    Article  CAS  PubMed  Google Scholar 

  20. Mendell, J. T. (2005). MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle, 4(9), 1179–1184.

    Article  CAS  PubMed  Google Scholar 

  21. Esteller, M. (2011). Non-coding RNAs in human disease. Nature Reviews. Genetics, 12(12), 861–874.

    Article  CAS  PubMed  Google Scholar 

  22. Liz, J., & Esteller, M. (2016). lncRNAs and microRNAs with a role in cancer development. Biochimica et Biophysica Acta, 1859(1), 169–176.

    Article  CAS  PubMed  Google Scholar 

  23. Askarian-Amiri, M. E., Crawford, J., French, J. D., Smart, C. E., Smith, M. A., Clark, M. B., Ru, K., Mercer, T. R., Thompson, E. R., Lakhani, S. R., Vargas, A. C., Campbell, I. G., Brown, M. A., Dinger, M. E., & Mattick, J. S. (2011). SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer. RNA, 17(5), 878–891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ronnau, C. G., Verhaegh, G. W., Luna-Velez, M. V., & Schalken, J. A. (2014). Noncoding RNAs as novel biomarkers in prostate cancer. BioMed Research International, 2014, 591703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fatima, R., Akhade, V. S., Pal, D., & Rao, S. M. (2015). Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets. Mol Cell Ther, 3, 5.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hayes, J., Peruzzi, P. P., & Lawler, S. (2014). MicroRNAs in cancer: biomarkers, functions and therapy. Trends in Molecular Medicine, 20(8), 460–469.

    Article  CAS  PubMed  Google Scholar 

  27. Lee, R. C., Feinbaum, R. L., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 75(5), 843–854.

    Article  CAS  PubMed  Google Scholar 

  28. Friedman, R. C., Farh, K. K., Burge, C. B., & Bartel, D. P. (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome Research, 19(1), 92–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Llave, C., Xie, Z., Kasschau, K. D., & Carrington, J. C. (2002). Cleavage of scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science, 297(5589), 2053–2056.

    Article  CAS  PubMed  Google Scholar 

  30. Valencia-Sanchez, M. A., Liu, J., Hannon, G. J., & Parker, R. (2006). Control of translation and mRNA degradation by miRNAs and siRNAs. Genes & Development, 20(5), 515–524.

    Article  CAS  Google Scholar 

  31. Zeng, Y., Yi, R., & Cullen, B. R. (2003). MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proceedings of the National Academy of Sciences of the United States of America, 100(17), 9779–9784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vagin, V. V., Sigova, A., Li, C., Seitz, H., Gvozdev, V., & Zamore, P. D. (2006). A distinct small RNA pathway silences selfish genetic elements in the germline. Science, 313(5785), 320–324.

    Article  CAS  PubMed  Google Scholar 

  33. Huang, X. A., Yin, H., Sweeney, S., Raha, D., Snyder, M., & Lin, H. (2013). A major epigenetic programming mechanism guided by piRNAs. Developmental Cell, 24(5), 502–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yin, H., & Lin, H. (2007). An epigenetic activation role of Piwi and a Piwi-associated piRNA in Drosophila melanogaster. Nature, 450(7167), 304–308.

    Article  CAS  PubMed  Google Scholar 

  35. Faulkner, G. J., Kimura, Y., Daub, C. O., Wani, S., Plessy, C., Irvine, K. M., Schroder, K., Cloonan, N., Steptoe, A. L., Lassmann, T., Waki, K., Hornig, N., Arakawa, T., Takahashi, H., Kawai, J., Forrest, A. R., Suzuki, H., Hayashizaki, Y., Hume, D. A., Orlando, V., Grimmond, S. M., & Carninci, P. (2009). The regulated retrotransposon transcriptome of mammalian cells. Nature Genetics, 41(5), 563–571.

    Article  CAS  PubMed  Google Scholar 

  36. Lim, A. K., Lorthongpanich, C., Chew, T. G., Tan, C. W., Shue, Y. T., Balu, S., Gounko, N., Kuramochi-Miyagawa, S., Matzuk, M. M., Chuma, S., Messerschmidt, D. M., Solter, D., & Knowles, B. B. (2013). The nuage mediates retrotransposon silencing in mouse primordial ovarian follicles. Development, 140(18), 3819–3825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martinez, V. D., Vucic, E. A., Thu, K. L., Hubaux, R., Enfield, K. S., Pikor, L. A., Becker-Santos, D. D., Brown, C. J., Lam, S., & Lam, W. L. (2015). Unique somatic and malignant expression patterns implicate PIWI-interacting RNAs in cancer-type specific biology. Scientific Reports, 5, 10423.

    Article  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. Cavaille, J., Nicoloso, M., & Bachellerie, J. P. (1996). Targeted ribose methylation of RNA in vivo directed by tailored antisense RNA guides. Nature, 383(6602), 732–735.

    Article  CAS  PubMed  Google Scholar 

  40. Ganot, P., Bortolin, M. L., & Kiss, T. (1997). Site-specific pseudouridine formation in preribosomal RNA is guided by small nucleolar RNAs. Cell, 89(5), 799–809.

    Article  CAS  PubMed  Google Scholar 

  41. Decatur, W. A., & Fournier, M. J. (2002). rRNA modifications and ribosome function. Trends in Biochemical Sciences, 27(7), 344–351.

    Article  CAS  PubMed  Google Scholar 

  42. Huang, C., Shi, J., Guo, Y., Huang, W., Huang, S., Ming, S., Wu, X., Zhang, R., Ding, J., Zhao, W., Jia, J., Huang, X., Xiang, A. P., Shi, Y., & Yao, C. (2017). A snoRNA modulates mRNA 3′ end processing and regulates the expression of a subset of mRNAs. Nucleic Acids Research, 45(15), 8647–8660.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gerbi, S. A. (1995). Small nucleolar RNA. Biochemistry and Cell Biology, 73(11–12), 845–858.

    Article  CAS  PubMed  Google Scholar 

  44. Kiss, T. (2001). Small nucleolar RNA-guided post-transcriptional modification of cellular RNAs. The EMBO Journal, 20(14), 3617–3622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fatica, A., & Bozzoni, I. (2014). Long non-coding RNAs: new players in cell differentiation and development. Nature Reviews. Genetics, 15(1), 7–21.

    Article  CAS  PubMed  Google Scholar 

  46. Hu, W., Alvarez-Dominguez, J. R., & Lodish, H. F. (2012). Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO Reports, 13(11), 971–983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Derrien, T., Johnson, R., Bussotti, G., Tanzer, A., Djebali, S., Tilgner, H., Guernec, G., Martin, D., Merkel, A., Knowles, D. G., Lagarde, J., Veeravalli, L., Ruan, X., Ruan, Y., Lassmann, T., Carninci, P., Brown, J. B., Lipovich, L., Gonzalez, J. M., Thomas, M., Davis, C. A., Shiekhattar, R., Gingeras, T. R., Hubbard, T. J., Notredame, C., Harrow, J., & Guigo, R. (2012). The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Research, 22(9), 1775–1789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim, T. K., Hemberg, M., Gray, J. M., Costa, A. M., Bear, D. M., Wu, J., Harmin, D. A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., Markenscoff-Papadimitriou, E., Kuhl, D., Bito, H., Worley, P. F., Kreiman, G., & Greenberg, M. E. (2010). Widespread transcription at neuronal activity-regulated enhancers. Nature, 465(7295), 182–187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Andersson, R., Gebhard, C., Miguel-Escalada, I., Hoof, I., Bornholdt, J., Boyd, M., Chen, Y., Zhao, X., Schmidl, C., Suzuki, T., Ntini, E., Arner, E., Valen, E., Li, K., Schwarzfischer, L., Glatz, D., Raithel, J., Lilje, B., Rapin, N., Bagger, F. O., Jorgensen, M., Andersen, P. R., Bertin, N., Rackham, O., Burroughs, A. M., Baillie, J. K., Ishizu, Y., Shimizu, Y., Furuhata, E., Maeda, S., Negishi, Y., Mungall, C. J., Meehan, T. F., Lassmann, T., Itoh, M., Kawaji, H., Kondo, N., Kawai, J., Lennartsson, A., Daub, C. O., Heutink, P., Hume, D. A., Jensen, T. H., Suzuki, H., Hayashizaki, Y., Muller, F., Forrest, A. R. R., Carninci, P., Rehli, M., & Sandelin, A. (2014). An atlas of active enhancers across human cell types and tissues. Nature, 507(7493), 455–461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N., & Kadener, S. (2014). circRNA biogenesis competes with pre-mRNA splicing. Molecular Cell, 56(1), 55–66.

    Article  CAS  PubMed  Google Scholar 

  51. Cocquerelle, C., Daubersies, P., Majerus, M. A., Kerckaert, J. P., & Bailleul, B. (1992). Splicing with inverted order of exons occurs proximal to large introns. The EMBO Journal, 11(3), 1095–1098.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E. (2013). Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA, 19(2), 141–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Guo, J. U., Agarwal, V., Guo, H., & Bartel, D. P. (2014). Expanded identification and characterization of mammalian circular RNAs. Genome Biology, 15(7), 409.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., Loewer, A., Ziebold, U., Landthaler, M., Kocks, C., le Noble, F., & Rajewsky, N. (2013). Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 495(7441), 333–338.

    Article  CAS  PubMed  Google Scholar 

  55. Salzman, J., Chen, R. E., Olsen, M. N., Wang, P. L., & Brown, P. O. (2013). Cell-type specific features of circular RNA expression. PLoS Genetics, 9(9), e1003777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013). Natural RNA circles function as efficient microRNA sponges. Nature, 495(7441), 384–388.

    Article  CAS  PubMed  Google Scholar 

  57. Hansen, T. B., Wiklund, E. D., Bramsen, J. B., Villadsen, S. B., Statham, A. L., Clark, S. J., & Kjems, J. (2011). miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. The EMBO Journal, 30(21), 4414–4422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li, Y., Zheng, Q., Bao, C., Li, S., Guo, W., Zhao, J., Chen, D., Gu, J., He, X., & Huang, S. (2015). Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Research, 25(8), 981–984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Guttman, M., & Rinn, J. L. (2012). Modular regulatory principles of large non-coding RNAs. Nature, 482(7385), 339–346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, K. C., Yang, Y. W., Liu, B., Sanyal, A., Corces-Zimmerman, R., Chen, Y., Lajoie, B. R., Protacio, A., Flynn, R. A., Gupta, R. A., Wysocka, J., Lei, M., Dekker, J., Helms, J. A., & Chang, H. Y. (2011). A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature, 472(7341), 120–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Boros, J., Arnoult, N., Stroobant, V., Collet, J. F., & Decottignies, A. (2014). Polycomb repressive complex 2 and H3K27me3 cooperate with H3K9 methylation to maintain heterochromatin protein 1alpha at chromatin. Molecular and Cellular Biology, 34(19), 3662–3674.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Rinn, J. L., Kertesz, M., Wang, J. K., Squazzo, S. L., Xu, X., Brugmann, S. A., Goodnough, L. H., Helms, J. A., Farnham, P. J., Segal, E., & Chang, H. Y. (2007). Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell, 129(7), 1311–1323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tsai, M. C., Manor, O., Wan, Y., Mosammaparast, N., Wang, J. K., Lan, F., Shi, Y., Segal, E., & Chang, H. Y. (2010). Long noncoding RNA as modular scaffold of histone modification complexes. Science, 329(5992), 689–693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brown, C. J., Ballabio, A., Rupert, J. L., Lafreniere, R. G., Grompe, M., Tonlorenzi, R., & Willard, H. F. (1991). A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature, 349(6304), 38–44.

    Article  CAS  PubMed  Google Scholar 

  65. Csankovszki, G., Nagy, A., & Jaenisch, R. (2001). Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. The Journal of Cell Biology, 153(4), 773–784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Navarro, P., Page, D. R., Avner, P., & Rougeulle, C. (2006). Tsix-mediated epigenetic switch of a CTCF-flanked region of the Xist promoter determines the Xist transcription program. Genes & Development, 20(20), 2787–2792.

    Article  CAS  Google Scholar 

  67. Chureau, C., Chantalat, S., Romito, A., Galvani, A., Duret, L., Avner, P., & Rougeulle, C. (2011). Ftx is a non-coding RNA which affects Xist expression and chromatin structure within the X-inactivation center region. Human Molecular Genetics, 20(4), 705–718.

    Article  CAS  PubMed  Google Scholar 

  68. Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J. F., Wyczalkowski, M. A., Leiserson, M. D. M., Miller, C. A., Welch, J. S., Walter, M. J., Wendl, M. C., Ley, T. J., Wilson, R. K., Raphael, B. J., & Ding, L. (2013). Mutational landscape and significance across 12 major cancer types. Nature, 502(7471), 333–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., & Dryja, T. P. (1986). A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature, 323(6089), 643–646.

    Article  CAS  PubMed  Google Scholar 

  70. Collins, S., & Groudine, M. (1982). Amplification of endogenous myc-related DNA sequences in a human myeloid leukaemia cell line. Nature, 298(5875), 679–681.

    Article  CAS  PubMed  Google Scholar 

  71. Meyer, C., Schneider, B., Jakob, S., Strehl, S., Attarbaschi, A., Schnittger, S., Schoch, C., Jansen, M. W., van Dongen, J. J., den Boer, M. L., Pieters, R., Ennas, M. G., Angelucci, E., Koehl, U., Greil, J., Griesinger, F., Zur Stadt, U., Eckert, C., Szczepanski, T., Niggli, F. K., Schafer, B. W., Kempski, H., Brady, H. J., Zuna, J., Trka, J., Nigro, L. L., Biondi, A., Delabesse, E., Macintyre, E., Stanulla, M., Schrappe, M., Haas, O. A., Burmeister, T., Dingermann, T., Klingebiel, T., & Marschalek, R. (2006). The MLL recombinome of acute leukemias. Leukemia, 20(5), 777–784.

    Article  CAS  PubMed  Google Scholar 

  72. Calin, G. A., Dumitru, C. D., Shimizu, M., Bichi, R., Zupo, S., Noch, E., Aldler, H., Rattan, S., Keating, M., Rai, K., Rassenti, L., Kipps, T., Negrini, M., Bullrich, F., & Croce, C. M. (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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cimmino, A., Calin, G. A., Fabbri, M., Iorio, M. V., Ferracin, M., Shimizu, M., Wojcik, S. E., Aqeilan, R. I., Zupo, S., Dono, M., Rassenti, L., Alder, H., Volinia, S., Liu, C. G., Kipps, T. J., Negrini, M., & Croce, C. M. (2005). miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the United States of America, 102(39), 13944–13949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Corney, D. C., Flesken-Nikitin, A., Godwin, A. K., Wang, W., & Nikitin, A. Y. (2007). MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Research, 67(18), 8433–8438.

    Article  CAS  PubMed  Google Scholar 

  75. Ota, A., Tagawa, H., Karnan, S., Tsuzuki, S., Karpas, A., Kira, S., Yoshida, Y., & Seto, M. (2004). Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Research, 64(9), 3087–3095.

    Article  CAS  PubMed  Google Scholar 

  76. Tagawa, H., Karube, K., Tsuzuki, S., Ohshima, K., & Seto, M. (2007). Synergistic action of the microRNA-17 polycistron and Myc in aggressive cancer development. Cancer Science, 98(9), 1482–1490.

    Article  CAS  PubMed  Google Scholar 

  77. Rao, E., Jiang, C., Ji, M., Huang, X., Iqbal, J., Lenz, G., Wright, G., Staudt, L. M., Zhao, Y., McKeithan, T. W., Chan, W. C., & Fu, K. (2012). The miRNA-17 approximately 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia, 26(5), 1064–1072.

    Article  CAS  PubMed  Google Scholar 

  78. Jiang, P., Rao, E. Y., Meng, N., Zhao, Y., & Wang, J. J. (2010). MicroRNA-17-92 significantly enhances radioresistance in human mantle cell lymphoma cells. Radiation Oncology, 5, 100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Czubak, K., Lewandowska, M. A., Klonowska, K., Roszkowski, K., Kowalewski, J., Figlerowicz, M., & Kozlowski, P. (2015). High copy number variation of cancer-related microRNA genes and frequent amplification of DICER1 and DROSHA in lung cancer. Oncotarget, 6(27), 23399–23416.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Jazdzewski, K., Murray, E. L., Franssila, K., Jarzab, B., Schoenberg, D. R., & de la Chapelle, A. (2008). Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 105(20), 7269–7274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Paranjape, T., Heneghan, H., Lindner, R., Keane, F. K., Hoffman, A., Hollestelle, A., Dorairaj, J., Geyda, K., Pelletier, C., Nallur, S., Martens, J. W., Hooning, M. J., Kerin, M., Zelterman, D., Zhu, Y., Tuck, D., Harris, L., Miller, N., Slack, F., & Weidhaas, J. (2011). A 3′-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis. The Lancet Oncology, 12(4), 377–386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kim, M., Chen, X., Chin, L. J., Paranjape, T., Speed, W. C., Kidd, K. K., Zhao, H., Weidhaas, J. B., & Slack, F. J. (2014). Extensive sequence variation in the 3′ untranslated region of the KRAS gene in lung and ovarian cancer cases. Cell Cycle, 13(6), 1030–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Siprashvili, Z., Webster, D. E., Johnston, D., Shenoy, R. M., Ungewickell, A. J., Bhaduri, A., Flockhart, R., Zarnegar, B. J., Che, Y., Meschi, F., Puglisi, J. D., & Khavari, P. A. (2016). The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer. Nature Genetics, 48(1), 53–58.

    Article  CAS  PubMed  Google Scholar 

  84. Dong, X. Y., Guo, P., Boyd, J., Sun, X., Li, Q., Zhou, W., & Dong, J. T. (2009). Implication of snoRNA U50 in human breast cancer. Journal of Genetics and Genomics, 36(8), 447–454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dong, X. Y., Rodriguez, C., Guo, P., Sun, X., Talbot, J. T., Zhou, W., Petros, J., Li, Q., Vessella, R. L., Kibel, A. S., Stevens, V. L., Calle, E. E., & Dong, J. T. (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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tanaka, R., Satoh, H., Moriyama, M., Satoh, K., Morishita, Y., Yoshida, S., Watanabe, T., Nakamura, Y., & Mori, S. (2000). Intronic U50 small-nucleolar-RNA (snoRNA) host gene of no protein-coding potential is mapped at the chromosome breakpoint t(3;6)(q27;q15) of human B-cell lymphoma. Genes to Cells, 5(4), 277–287.

    Article  CAS  PubMed  Google Scholar 

  87. Mei, Y. P., Liao, J. P., Shen, J., Yu, L., Liu, B. L., Liu, L., Li, R. Y., Ji, L., Dorsey, S. G., Jiang, Z. R., Katz, R. L., Wang, J. Y., & Jiang, F. (2012). Small nucleolar RNA 42 acts as an oncogene in lung tumorigenesis. Oncogene, 31(22), 2794–2804.

    Article  CAS  PubMed  Google Scholar 

  88. Alter, B. P., Giri, N., Savage, S. A., & Rosenberg, P. S. (2009). Cancer in dyskeratosis congenita. Blood, 113(26), 6549–6557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Montanaro, L., Trere, D., & Derenzini, M. (2008). Nucleolus, ribosomes, and cancer. The American Journal of Pathology, 173(2), 301–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shiue, C. N., Berkson, R. G., & Wright, A. P. (2009). c-Myc induces changes in higher order rDNA structure on stimulation of quiescent cells. Oncogene, 28(16), 1833–1842.

    Article  CAS  PubMed  Google Scholar 

  91. Jiang, Z., Zhou, Y., Devarajan, K., Slater, C. M., Daly, M. B., & Chen, X. (2012). Identifying putative breast cancer-associated long intergenic non-coding RNA loci by high density SNP array analysis. Frontiers in Genetics, 3, 299.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Yan, X., Hu, Z., Feng, Y., Hu, X., Yuan, J., Zhao, S. D., Zhang, Y., Yang, L., Shan, W., He, Q., Fan, L., Kandalaft, L. E., Tanyi, J. L., Li, C., Yuan, C. X., Zhang, D., Yuan, H., Hua, K., Lu, Y., Katsaros, D., Huang, Q., Montone, K., Fan, Y., Coukos, G., Boyd, J., Sood, A. K., Rebbeck, T., Mills, G. B., Dang, C. V., & Zhang, L. (2015). Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell, 28(4), 529–540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hu, X., Feng, Y., Zhang, D., Zhao, S. D., Hu, Z., Greshock, J., Zhang, Y., Yang, L., Zhong, X., Wang, L. P., Jean, S., Li, C., Huang, Q., Katsaros, D., Montone, K. T., Tanyi, J. L., Lu, Y., Boyd, J., Nathanson, K. L., Li, H., Mills, G. B., & Zhang, L. (2014). A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell, 26(3), 344–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Du, Z., Fei, T., Verhaak, R. G., Su, Z., Zhang, Y., Brown, M., Chen, Y., & Liu, X. S. (2013). Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nature Structural & Molecular Biology, 20(7), 908–913.

    Article  CAS  Google Scholar 

  95. Pandey, G. K., Mitra, S., Subhash, S., Hertwig, F., Kanduri, M., Mishra, K., Fransson, S., Ganeshram, A., Mondal, T., Bandaru, S., Ostensson, M., Akyurek, L. M., Abrahamsson, J., Pfeifer, S., Larsson, E., Shi, L., Peng, Z., Fischer, M., Martinsson, T., Hedborg, F., Kogner, P., & Kanduri, C. (2014). The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. Cancer Cell, 26(5), 722–737.

    Article  CAS  PubMed  Google Scholar 

  96. Oey, H., & Whitelaw, E. (2014). On the meaning of the word ‘epimutation’. Trends in Genetics, 30(12), 519–520.

    Article  CAS  PubMed  Google Scholar 

  97. Hanada, M., Delia, D., Aiello, A., Stadtmauer, E., & Reed, J. C. (1993). bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood, 82(6), 1820–1828.

    CAS  PubMed  Google Scholar 

  98. Esteller, M., Silva, J. M., Dominguez, G., Bonilla, F., Matias-Guiu, X., Lerma, E., Bussaglia, E., Prat, J., Harkes, I. C., Repasky, E. A., Gabrielson, E., Schutte, M., Baylin, S. B., & Herman, J. G. (2000). Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. Journal of the National Cancer Institute, 92(7), 564–569.

    Article  CAS  PubMed  Google Scholar 

  99. Heyn, H., Vidal, E., Ferreira, H. J., Vizoso, M., Sayols, S., Gomez, A., Moran, S., Boque-Sastre, R., Guil, S., Martinez-Cardus, A., Lin, C. Y., Royo, R., Sanchez-Mut, J. V., Martinez, R., Gut, M., Torrents, D., Orozco, M., Gut, I., Young, R. A., & Esteller, M. (2016). Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biology, 17, 11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Datta, J., Kutay, H., Nasser, M. W., Nuovo, G. J., Wang, B., Majumder, S., Liu, C. G., Volinia, S., Croce, C. M., Schmittgen, T. D., Ghoshal, K., & Jacob, S. T. (2008). Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Research, 68(13), 5049–5058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Suzuki, H., Takatsuka, S., Akashi, H., Yamamoto, E., Nojima, M., Maruyama, R., Kai, M., Yamano, H. O., Sasaki, Y., Tokino, T., Shinomura, Y., Imai, K., & Toyota, M. (2011). Genome-wide profiling of chromatin signatures reveals epigenetic regulation of microRNA genes in colorectal cancer. Cancer Research, 71(17), 5646–5658.

    Article  CAS  PubMed  Google Scholar 

  102. Chen, W. S., Leung, C. M., Pan, H. W., Hu, L. Y., Li, S. C., Ho, M. R., & Tsai, K. W. (2012). Silencing of miR-1-1 and miR-133a-2 cluster expression by DNA hypermethylation in colorectal cancer. Oncology Reports, 28(3), 1069–1076.

    Article  CAS  PubMed  Google Scholar 

  103. He, X. X., Kuang, S. Z., Liao, J. Z., Xu, C. R., Chang, Y., Wu, Y. L., Gong, J., Tian, D. A., Guo, A. Y., & Lin, J. S. (2015). The regulation of microRNA expression by DNA methylation in hepatocellular carcinoma. Molecular BioSystems, 11(2), 532–539.

    Article  CAS  PubMed  Google Scholar 

  104. Dudziec, E., Miah, S., Choudhry, H. M., Owen, H. C., Blizard, S., Glover, M., Hamdy, F. C., & Catto, J. W. (2011). Hypermethylation of CpG islands and shores around specific microRNAs and mirtrons is associated with the phenotype and presence of bladder cancer. Clinical Cancer Research, 17(6), 1287–1296.

    Article  CAS  PubMed  Google Scholar 

  105. Lujambio, A., Ropero, S., Ballestar, E., Fraga, M. F., Cerrato, C., Setien, F., Casado, S., Suarez-Gauthier, A., Sanchez-Cespedes, M., Git, A., Spiteri, I., Das, P. P., Caldas, C., Miska, E., & Esteller, M. (2007). Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Research, 67(4), 1424–1429.

    Article  CAS  PubMed  Google Scholar 

  106. Furuta, M., Kozaki, K. I., Tanaka, S., Arii, S., Imoto, I., & Inazawa, J. (2010). miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis, 31(5), 766–776.

    Article  CAS  PubMed  Google Scholar 

  107. Wilting, S. M., van Boerdonk, R. A., Henken, F. E., Meijer, C. J., Diosdado, B., Meijer, G. A., le Sage, C., Agami, R., Snijders, P. J., & Steenbergen, R. D. (2010). Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Molecular Cancer, 9, 167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Lv, X. B., Jiao, Y., Qing, Y., Hu, H., Cui, X., Lin, T., Song, E., & Yu, F. (2011). miR-124 suppresses multiple steps of breast cancer metastasis by targeting a cohort of pro-metastatic genes in vitro. Chinese Journal of Cancer, 30(12), 821–830.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Wang, P., Chen, L., Zhang, J., Chen, H., Fan, J., Wang, K., Luo, J., Chen, Z., Meng, Z., & Liu, L. (2014). Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1. Oncogene, 33(4), 514–524.

    Article  CAS  PubMed  Google Scholar 

  110. Chen, X., He, D., Dong, X. D., Dong, F., Wang, J., Wang, L., Tang, J., Hu, D. N., Yan, D., & Tu, L. (2013). MicroRNA-124a is epigenetically regulated and acts as a tumor suppressor by controlling multiple targets in uveal melanoma. Investigative Ophthalmology & Visual Science, 54(3), 2248–2256.

    Article  CAS  Google Scholar 

  111. Tivnan, A., Zhao, J., Johns, T. G., Day, B. W., Stringer, B. W., Boyd, A. W., Tiwari, S., Giles, K. M., Teo, C., & McDonald, K. L. (2014). The tumor suppressor microRNA, miR-124a, is regulated by epigenetic silencing and by the transcriptional factor, REST in glioblastoma. Tumour Biology, 35(2), 1459–1465.

    Article  CAS  PubMed  Google Scholar 

  112. Formosa, A., Lena, A. M., Markert, E. K., Cortelli, S., Miano, R., Mauriello, A., Croce, N., Vandesompele, J., Mestdagh, P., Finazzi-Agro, E., Levine, A. J., Melino, G., Bernardini, S., & Candi, E. (2013). DNA methylation silences miR-132 in prostate cancer. Oncogene, 32(1), 127–134.

    Article  CAS  PubMed  Google Scholar 

  113. Qin, J., Ke, J., Xu, J., Wang, F., Zhou, Y., Jiang, Y., & Wang, Z. (2015). Downregulation of microRNA-132 by DNA hypermethylation is associated with cell invasion in colorectal cancer. Onco Targets Ther, 8, 3639–3648.

    PubMed  PubMed Central  Google Scholar 

  114. Zhang, S., Hao, J., Xie, F., Hu, X., Liu, C., Tong, J., Zhou, J., Wu, J., & Shao, C. (2011). Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development. Carcinogenesis, 32(8), 1183–1189.

    Article  CAS  PubMed  Google Scholar 

  115. Lin L, Wang Z, Jin H, Shi H, Lu Z, Qi Z (2016) MiR-212/132 is epigenetically downregulated by SOX4/EZH2-H3K27me3 feedback loop in ovarian cancer cells. Tumour Biol. 37(12), 15719–15727.

    Article  CAS  Google Scholar 

  116. Rani, S. B., Rathod, S. S., Karthik, S., Kaur, N., Muzumdar, D., & Shiras, A. S. (2013). MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. Neuro-Oncology, 15(10), 1302–1316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. He, Y., Cui, Y., Wang, W., Gu, J., Guo, S., Ma, K., & Luo, X. (2011). Hypomethylation of the hsa-miR-191 locus causes high expression of hsa-mir-191 and promotes the epithelial-to-mesenchymal transition in hepatocellular carcinoma. Neoplasia, 13(9), 841–853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Davalos, V., Moutinho, C., Villanueva, A., Boque, R., Silva, P., Carneiro, F., & Esteller, M. (2012). Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene, 31(16), 2062–2074.

    Article  CAS  PubMed  Google Scholar 

  119. Toyota, M., Suzuki, H., Sasaki, Y., Maruyama, R., Imai, K., Shinomura, Y., & Tokino, T. (2008). Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Cancer Research, 68(11), 4123–4132.

    Article  CAS  PubMed  Google Scholar 

  120. Xie, K., Liu, J., Chen, J., Dong, J., Ma, H., Liu, Y., & Hu, Z. (2014). Methylation-associated silencing of microRNA-34b in hepatocellular carcinoma cancer. Gene, 543(1), 101–107.

    Article  CAS  PubMed  Google Scholar 

  121. Daugaard, I., Knudsen, A., Kjeldsen, T. E., Hager, H., & Hansen, L. L. (2017). The association between miR-34 dysregulation and distant metastases formation in lung adenocarcinoma. Experimental and Molecular Pathology, 102(3), 484–491.

    Article  CAS  PubMed  Google Scholar 

  122. Zhang, X., Gejman, R., Mahta, A., Zhong, Y., Rice, K. A., Zhou, Y., Cheunsuchon, P., Louis, D. N., & Klibanski, A. (2010). Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Research, 70(6), 2350–2358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wu, Y., Lyu, H., Liu, H., Shi, X., Song, Y., & Liu, B. (2016). Downregulation of the long noncoding RNA GAS5-AS1 contributes to tumor metastasis in non-small cell lung cancer. Scientific Reports, 6, 31093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Diaz-Lagares, A., Crujeiras, A. B., Lopez-Serra, P., Soler, M., Setien, F., Goyal, A., Sandoval, J., Hashimoto, Y., Martinez-Cardus, A., Gomez, A., Heyn, H., Moutinho, C., Espada, J., Vidal, A., Paules, M., Galan, M., Sala, N., Akiyama, Y., Martinez-Iniesta, M., Farre, L., Villanueva, A., Gross, M., Diederichs, S., Guil, S., & Esteller, M. (2016). Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(47), E7535–E7544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Boque-Sastre, R., Soler, M., Oliveira-Mateos, C., Portela, A., Moutinho, C., Sayols, S., Villanueva, A., Esteller, M., & Guil, S. (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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ferreira, H. J., Heyn, H., Moutinho, C., & Esteller, M. (2012). CpG island hypermethylation-associated silencing of small nucleolar RNAs in human cancer. RNA Biology, 9(6), 881–890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lujambio, A., Portela, A., Liz, J., Melo, S. A., Rossi, S., Spizzo, R., Croce, C. M., Calin, G. A., & Esteller, M. (2010). CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Oncogene, 29(48), 6390–6401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Cao, J. (2014). The functional role of long non-coding RNAs and epigenetics. Biol Proced Online, 16, 11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Suzuki, H., Maruyama, R., Yamamoto, E., & Kai, M. (2012). DNA methylation and microRNA dysregulation in cancer. Molecular Oncology, 6(6), 567–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lopez-Serra, P., & Esteller, M. (2012). DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer. Oncogene, 31(13), 1609–1622.

    Article  CAS  PubMed  Google Scholar 

  131. Ehrlich, M. (2009). DNA hypomethylation in cancer cells. Epigenomics, 1(2), 239–259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Urdinguio, R. G., Fernandez, A. F., Lopez-Nieva, P., Rossi, S., Huertas, D., Kulis, M., Liu, C. G., Croce, C. M., Calin, G. A., & Esteller, M. (2010). Disrupted microRNA expression caused by Mecp2 loss in a mouse model of Rett syndrome. Epigenetics, 5(7), 656–663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Qu, W., Ding, S. M., Cao, G., Wang, S. J., Zheng, X. H., & Li, G. H. (2016). miR-132 mediates a metabolic shift in prostate cancer cells by targeting Glut1. FEBS Open Bio, 6(7), 735–741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013). Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell, 153(2), 307–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hnisz, D., Abraham, B. J., Lee, T. I., Lau, A., Saint-Andre, V., Sigova, A. A., Hoke, H. A., & Young, R. A. (2013). Super-enhancers in the control of cell identity and disease. Cell, 155(4), 934–947.

    Article  CAS  PubMed  Google Scholar 

  136. Loven, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013). Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell, 153(2), 320–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.

    Article  CAS  PubMed  Google Scholar 

  138. Ruby, J. G., Jan, C. H., & Bartel, D. P. (2007). Intronic microRNA precursors that bypass Drosha processing. Nature, 448(7149), 83–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wu, Q., Ma, Q., Shehadeh, L. A., Wilson, A., Xia, L., Yu, H., & Webster, K. A. (2010). Expression of the Argonaute protein PiwiL2 and piRNAs in adult mouse mesenchymal stem cells. Biochemical and Biophysical Research Communications, 396(4), 915–920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Iliev, R., Stanik, M., Fedorko, M., Poprach, A., Vychytilova-Faltejskova, P., Slaba, K., Svoboda, M., Fabian, P., Pacik, D., Dolezel, J., & Slaby, O. (2016). Decreased expression levels of PIWIL1, PIWIL2, and PIWIL4 are associated with worse survival in renal cell carcinoma patients. Onco Targets Ther, 9, 217–222.

    PubMed  PubMed Central  Google Scholar 

  141. Greither, T., Koser, F., Kappler, M., Bache, M., Lautenschlager, C., Gobel, S., Holzhausen, H. J., Wach, S., Wurl, P., & Taubert, H. (2012). Expression of human Piwi-like genes is associated with prognosis for soft tissue sarcoma patients. BMC Cancer, 12, 272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Navarro, A., Tejero, R., Vinolas, N., Cordeiro, A., Marrades, R. M., Fuster, D., Caritg, O., Moises, J., Munoz, C., Molins, L., Ramirez, J., & Monzo, M. (2015). The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer. Oncotarget, 6(31), 31544–31556.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Bamezai, S., Rawat, V. P., & Buske, C. (2012). Concise review: The Piwi-piRNA axis: pivotal beyond transposon silencing. Stem Cells, 30(12), 2603–2611.

    Article  CAS  PubMed  Google Scholar 

  144. Ferreira, H. J., Heyn, H., Garcia del Muro, X., Vidal, A., Larriba, S., Munoz, C., Villanueva, A., & Esteller, M. (2014). Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis. Epigenetics, 9(1), 113–118.

    Article  CAS  PubMed  Google Scholar 

  145. Rounge, T. B., Furu, K., Skotheim, R. I., Haugen, T. B., Grotmol, T., & Enerly, E. (2015). Profiling of the small RNA populations in human testicular germ cell tumors shows global loss of piRNAs. Molecular Cancer, 14, 153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ushida, H., Kawakami, T., Minami, K., Chano, T., Okabe, H., Okada, Y., & Okamoto, K. (2012). Methylation profile of DNA repetitive elements in human testicular germ cell tumor. Molecular Carcinogenesis, 51(9), 711–722.

    Article  CAS  PubMed  Google Scholar 

  147. Heyn, H., Ferreira, H. J., Bassas, L., Bonache, S., Sayols, S., Sandoval, J., Esteller, M., & Larriba, S. (2012). Epigenetic disruption of the PIWI pathway in human spermatogenic disorders. PLoS One, 7(10), e47892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hotaling, J. M., & Walsh, T. J. (2009). Male infertility: a risk factor for testicular cancer. Nature Reviews. Urology, 6(10), 550–556.

    Article  CAS  PubMed  Google Scholar 

  149. Peng, X., Zeng, X., Peng, S., Deng, D., & Zhang, J. (2009). The association risk of male subfertility and testicular cancer: a systematic review. PLoS One, 4(5), e5591.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Liz, J., Portela, A., Soler, M., Gomez, A., Ling, H., Michlewski, G., Calin, G. A., Guil, S., & Esteller, M. (2014). Regulation of pri-miRNA processing by a long noncoding RNA transcribed from an ultraconserved region. Molecular Cell, 55(1), 138–147.

    Article  CAS  PubMed  Google Scholar 

  151. Ronchetti, D., Mosca, L., Cutrona, G., Tuana, G., Gentile, M., Fabris, S., Agnelli, L., Ciceri, G., Matis, S., Massucco, C., Colombo, M., Reverberi, D., Recchia, A. G., Bossio, S., Negrini, M., Tassone, P., Morabito, F., Ferrarini, M., & Neri, A. (2013). Small nucleolar RNAs as new biomarkers in chronic lymphocytic leukemia. BMC Medical Genomics, 6, 27.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Bellodi, C., McMahon, M., Contreras, A., Juliano, D., Kopmar, N., Nakamura, T., Maltby, D., Burlingame, A., Savage, S. A., Shimamura, A., & Ruggero, D. (2013). H/ACA small RNA dysfunctions in disease reveal key roles for noncoding RNA modifications in hematopoietic stem cell differentiation. Cell Reports, 3(5), 1493–1502.

    Article  CAS  PubMed  Google Scholar 

  153. McMahon, M., Ayllon, V., Panov, K. I., & O'Connor, R. (2010). Ribosomal 18 S RNA processing by the IGF-I-responsive WDR3 protein is integrated with p53 function in cancer cell proliferation. The Journal of Biological Chemistry, 285(24), 18309–18318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Peng, Q., Wu, J., Zhang, Y., Liu, Y., Kong, R., Hu, L., Du, X., & Ke, Y. (2010). 1A6/DRIM, a novel t-UTP, activates RNA polymerase I transcription and promotes cell proliferation. PLoS One, 5(12), e14244.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. 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.

    Article  CAS  PubMed  Google Scholar 

  156. Valleron, W., Laprevotte, E., Gautier, E. F., Quelen, C., Demur, C., Delabesse, E., Agirre, X., Prosper, F., Kiss, T., & Brousset, P. (2012). Specific small nucleolar RNA expression profiles in acute leukemia. Leukemia, 26(9), 2052–2060.

    Article  CAS  PubMed  Google Scholar 

  157. Ono, M., Yamada, K., Avolio, F., Scott, M. S., van Koningsbruggen, S., Barton, G. J., & Lamond, A. I. (2010). Analysis of human small nucleolar RNAs (snoRNA) and the development of snoRNA modulator of gene expression vectors. Molecular Biology of the Cell, 21(9), 1569–1584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Mourtada-Maarabouni, M., Pickard, M. R., Hedge, V. L., Farzaneh, F., & Williams, G. T. (2009). GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene, 28(2), 195–208.

    Article  CAS  PubMed  Google Scholar 

  160. 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.

    Article  CAS  PubMed  Google Scholar 

  161. Qiao, H. P., Gao, W. S., Huo, J. X., & Yang, Z. S. (2013). Long non-coding RNA GAS5 functions as a tumor suppressor in renal cell carcinoma. Asian Pacific Journal of Cancer Prevention, 14(2), 1077–1082.

    Article  PubMed  Google Scholar 

  162. Lu, X., Fang, Y., Wang, Z., Xie, J., Zhan, Q., Deng, X., Chen, H., Jin, J., Peng, C., Li, H., & Shen, B. (2013). Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6. Cell and Tissue Research, 354(3), 891–896.

    Article  CAS  PubMed  Google Scholar 

  163. Liu, Z., Wang, W., Jiang, J., Bao, E., Xu, D., Zeng, Y., Tao, L., & Qiu, J. (2013). Downregulation of GAS5 promotes bladder cancer cell proliferation, partly by regulating CDK6. PLoS One, 8(9), e73991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Shi, X., Sun, M., Liu, H., Yao, Y., Kong, R., Chen, F., & Song, Y. (2015). A critical role for the long non-coding RNA GAS5 in proliferation and apoptosis in non-small-cell lung cancer. Molecular Carcinogenesis, 54(Suppl 1), E1–E12.

    Article  CAS  PubMed  Google Scholar 

  165. Sun, M., Jin, F. Y., Xia, R., Kong, R., Li, J. H., Xu, T. P., Liu, Y. W., Zhang, E. B., Liu, X. H., & De, W. (2014). Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer. BMC Cancer, 14, 319.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Yin, D., He, X., Zhang, E., Kong, R., De, W., & Zhang, Z. (2014). Long noncoding RNA GAS5 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Medical Oncology, 31(11), 253.

    Article  PubMed  CAS  Google Scholar 

  167. Cao, S., Liu, W., Li, F., Zhao, W., & Qin, C. (2014). Decreased expression of lncRNA GAS5 predicts a poor prognosis in cervical cancer. International Journal of Clinical and Experimental Pathology, 7(10), 6776–6783.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Yu, F., Zheng, J., Mao, Y., Dong, P., Lu, Z., Li, G., Guo, C., Liu, Z., & Fan, X. (2015). Long non-coding RNA growth arrest-specific transcript 5 (GAS5) inhibits liver fibrogenesis through a mechanism of competing endogenous RNA. The Journal of Biological Chemistry, 290(47), 28286–28298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Luo, G., Liu, D., Huang, C., Wang, M., Xiao, X., Zeng, F., Wang, L., & Jiang, G. (2017). LncRNA GAS5 inhibits cellular proliferation by targeting P27Kip1. Molecular Cancer Research, 15(7), 789–799.

    Article  CAS  PubMed  Google Scholar 

  170. Zhang, Z., Zhu, Z., Watabe, K., Zhang, X., Bai, C., Xu, M., Wu, F., & Mo, Y. Y. (2013). Negative regulation of lncRNA GAS5 by miR-21. Cell Death and Differentiation, 20(11), 1558–1568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Jelinic, P., & Shaw, P. (2007). Loss of imprinting and cancer. The Journal of Pathology, 211(3), 261–268.

    Article  CAS  PubMed  Google Scholar 

  172. da Rocha, S. T., Edwards, C. A., Ito, M., Ogata, T., & Ferguson-Smith, A. C. (2008). Genomic imprinting at the mammalian Dlk1-Dio3 domain. Trends in Genetics, 24(6), 306–316.

    Article  PubMed  CAS  Google Scholar 

  173. Molina-Pinelo S SA, Moreno-Mata N, Ferrer I, Suarez R, Andres-Leon E, Rodriguez-Paredes M, Gutekunst J, Jantus-Lewintre E, Camps C, Carnero A, Paz-Ares L (2016) Impact of DLK1–DIO3 imprinted cluster hypomethylation in smoker patients with lung cancer. Oncotarget https://doi.org/10.18632/oncotarget.10611.

  174. Nadal, E., Zhong, J., Lin, J., Reddy, R. M., Ramnath, N., Orringer, M. B., Chang, A. C., Beer, D. G., & Chen, G. (2014). A microRNA cluster at 14q32 drives aggressive lung adenocarcinoma. Clinical Cancer Research, 20(12), 3107–3117.

    Article  CAS  PubMed  Google Scholar 

  175. Luk, J. M., Burchard, J., Zhang, C., Liu, A. M., Wong, K. F., Shek, F. H., Lee, N. P., Fan, S. T., Poon, R. T., Ivanovska, I., Philippar, U., Cleary, M. A., Buser, C. A., Shaw, P. M., Lee, C. N., Tenen, D. G., Dai, H., & Mao, M. (2011). DLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival. The Journal of Biological Chemistry, 286(35), 30706–30713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Devor, E. J., JN, D. E. M., Ramachandran, S., Goodheart, M. J., & Leslie, K. K. (2012). Global dysregulation of the chromosome 14q32 imprinted region in uterine carcinosarcoma. Experimental and Therapeutic Medicine, 3(4), 677–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. El-Daly, S. M., Abba, M. L., Patil, N., & Allgayer, H. (2016). miRs-134 and -370 function as tumor suppressors in colorectal cancer by independently suppressing EGFR and PI3K signalling. Scientific Reports, 6, 24720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Azarbarzin, S., Hosseinpour Feizi, M. A., Safaralizadeh, R., Ravanbakhsh, R., Kazemzadeh, M., Fateh, A., Karimi, N., & Moaddab, Y. (2016). The value of miR-299-5p in diagnosis and prognosis of intestinal-type gastric adenocarcinoma. Biochemical Genetics, 54(4), 413–420.

    Article  CAS  PubMed  Google Scholar 

  179. Lucon, D. R., Rocha Cde, S., Craveiro, R. B., Dilloo, D., Cardinalli, I. A., Cavalcanti, D. P., Aguiar Sdos, S., Maurer-Morelli, C., & Yunes, J. A. (2013). Downregulation of 14q32 microRNAs in primary human desmoplastic medulloblastoma. Frontiers in Oncology, 3, 254.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Geraldo, M. V., Nakaya, H. I., & Kimura, E. T. (2017). Down-regulation of 14q32-encoded miRNAs and tumor suppressor role for miR-654-3p in papillary thyroid cancer. Oncotarget, 8(6), 9597–9607.

    Article  PubMed  Google Scholar 

  181. Laddha, S. V., Nayak, S., Paul, D., Reddy, R., Sharma, C., Jha, P., Hariharan, M., Agrawal, A., Chowdhury, S., Sarkar, C., & Mukhopadhyay, A. (2013). Genome-wide analysis reveals downregulation of miR-379/miR-656 cluster in human cancers. Biology Direct, 8, 10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Tsang, E. K., Abell, N. S., Li, X., Anaya, V., Karczewski, K. J., Knowles, D. A., Sierra, R. G., Smith, K. S., & Montgomery, S. B. (2017). Small RNA sequencing in cells and exosomes identifies eQTLs and 14q32 as a region of active export. G3 (Bethesda), 7(1), 31–39.

    Article  Google Scholar 

  183. Enfield, K. S., Martinez, V. D., Marshall, E. A., Stewart, G. L., Kung, S. H., Enterina, J. R., & Lam, W. L. (2016). Deregulation of small non-coding RNAs at the DLK1-DIO3 imprinted locus predicts lung cancer patient outcome. Oncotarget, 7(49), 80957–80966.

    Article  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  185. Amente, S., Bertoni, A., Morano, A., Lania, L., Avvedimento, E. V., & Majello, B. (2010). LSD1-mediated demethylation of histone H3 lysine 4 triggers Myc-induced transcription. Oncogene, 29(25), 3691–3702.

    Article  CAS  PubMed  Google Scholar 

  186. Li, Y., Wang, Z., Shi, H., Li, H., Li, L., Fang, R., Cai, X., Liu, B., Zhang, X., & Ye, L. (2016). HBXIP and LSD1 scaffolded by lncRNA hotair mediate transcriptional activation by c-Myc. Cancer Research, 76(2), 293–304.

    Article  CAS  PubMed  Google Scholar 

  187. Ge, X. S., Ma, H. J., Zheng, X. H., Ruan, H. L., Liao, X. Y., Xue, W. Q., Chen, Y. B., Zhang, Y., & Jia, W. H. (2013). HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway. Cancer Science, 104(12), 1675–1682.

    Article  CAS  PubMed  Google Scholar 

  188. Liu, X. H., Sun, M., Nie, F. Q., Ge, Y. B., Zhang, E. B., Yin, D. D., Kong, R., Xia, R., Lu, K. H., Li, J. H., De, W., Wang, K. M., & Wang, Z. X. (2014). Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Molecular Cancer, 13, 92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bian, E. B., Ma, C. C., He, X. J., Wang, C., Zong, G., Wang, H. L., & Zhao, B. (2016). Epigenetic modification of miR-141 regulates SKA2 by an endogenous ‘sponge’ HOTAIR in glioma. Oncotarget, 7(21), 30610–30625.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Song, B., Guan, Z., Liu, F., Sun, D., Wang, K., & Qu, H. (2015). Long non-coding RNA HOTAIR promotes HLA-G expression via inhibiting miR-152 in gastric cancer cells. Biochemical and Biophysical Research Communications, 464(3), 807–813.

    Article  CAS  PubMed  Google Scholar 

  191. Xu, F., & Zhang, J. (2017). Long non-coding RNA HOTAIR functions as miRNA sponge to promote the epithelial to mesenchymal transition in esophageal cancer. Biomedicine & Pharmacotherapy, 90, 888–896.

    Article  CAS  Google Scholar 

  192. Garzon, R., Liu, S., Fabbri, M., Liu, Z., Heaphy, C. E., Callegari, E., Schwind, S., Pang, J., Yu, J., Muthusamy, N., Havelange, V., Volinia, S., Blum, W., Rush, L. J., Perrotti, D., Andreeff, M., Bloomfield, C. D., Byrd, J. C., Chan, K., Wu, L. C., Croce, C. M., & Marcucci, G. (2009). MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood, 113(25), 6411–6418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Cheng, J., Guo, S., Chen, S., Mastriano, S. J., Liu, C., D'Alessio, A. C., Hysolli, E., Guo, Y., Yao, H., Megyola, C. M., Li, D., Liu, J., Pan, W., Roden, C. A., Zhou, X. L., Heydari, K., Chen, J., Park, I. H., Ding, Y., Zhang, Y., & Lu, J. (2013). An extensive network of TET2-targeting MicroRNAs regulates malignant hematopoiesis. Cell Reports, 5(2), 471–481.

    Article  CAS  PubMed  Google Scholar 

  194. Garzon, R., Volinia, S., Liu, C. G., Fernandez-Cymering, C., Palumbo, T., Pichiorri, F., Fabbri, M., Coombes, K., Alder, H., Nakamura, T., Flomenberg, N., Marcucci, G., Calin, G. A., Kornblau, S. M., Kantarjian, H., Bloomfield, C. D., Andreeff, M., & Croce, C. M. (2008). MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood, 111(6), 3183–3189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Gupta, R. A., Shah, N., Wang, K. C., Kim, J., Horlings, H. M., Wong, D. J., Tsai, M. C., Hung, T., Argani, P., Rinn, J. L., Wang, Y., Brzoska, P., Kong, B., Li, R., West, R. B., van de Vijver, M. J., Sukumar, S., & Chang, H. Y. (2010). Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature, 464(7291), 1071–1076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Kogo, R., Shimamura, T., Mimori, K., Kawahara, K., Imoto, S., Sudo, T., Tanaka, F., Shibata, K., Suzuki, A., Komune, S., Miyano, S., & Mori, M. (2011). Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Research, 71(20), 6320–6326.

    Article  CAS  PubMed  Google Scholar 

  197. Wu, Z. H., Wang, X. L., Tang, H. M., Jiang, T., Chen, J., Lu, S., Qiu, G. Q., Peng, Z. H., & Yan, D. W. (2014). Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer. Oncology Reports, 32(1), 395–402.

    Article  CAS  PubMed  Google Scholar 

  198. Pistoia, V., Morandi, F., Wang, X., & Ferrone, S. (2007). Soluble HLA-G: are they clinically relevant? Seminars in Cancer Biology, 17(6), 469–479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Guil, S., Soler, M., Portela, A., Carrere, J., Fonalleras, E., Gomez, A., Villanueva, A., & Esteller, M. (2012). Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nature Structural & Molecular Biology, 19(7), 664–670.

    Article  CAS  Google Scholar 

  200. Zhang, Z., Weaver, D. L., Olsen, D., deKay, J., Peng, Z., Ashikaga, T., & Evans, M. F. (2016). Long non-coding RNA chromogenic in situ hybridisation signal pattern correlation with breast tumour pathology. Journal of Clinical Pathology, 69(1), 76–81.

    Article  CAS  PubMed  Google Scholar 

  201. Thorenoor, N., Faltejskova-Vychytilova, P., Hombach, S., Mlcochova, J., Kretz, M., Svoboda, M., & Slaby, O. (2016). Long non-coding RNA ZFAS1 interacts with CDK1 and is involved in p53-dependent cell cycle control and apoptosis in colorectal cancer. Oncotarget, 7(1), 622–637.

    Article  PubMed  Google Scholar 

  202. Li, T., Xie, J., Shen, C., Cheng, D., Shi, Y., Wu, Z., Deng, X., Chen, H., Shen, B., Peng, C., Li, H., Zhan, Q., & Zhu, Z. (2015). Amplification of long noncoding RNA ZFAS1 promotes metastasis in hepatocellular carcinoma. Cancer Research, 75(15), 3181–3191.

    Article  CAS  PubMed  Google Scholar 

  203. Wang, T., Ma, S., Qi, X., Tang, X., Cui, D., Wang, Z., Chi, J., Li, P., & Zhai, B. (2016). Long noncoding RNA ZNFX1-AS1 suppresses growth of hepatocellular carcinoma cells by regulating the methylation of miR-9. Onco Targets Ther, 9, 5005–5014.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Cai, L., & Cai, X. (2014). Up-regulation of miR-9 expression predicate advanced clinicopathological features and poor prognosis in patients with hepatocellular carcinoma. Diagnostic Pathology, 9, 1000.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Ma, L., Young, J., Prabhala, H., Pan, E., Mestdagh, P., Muth, D., Teruya-Feldstein, J., Reinhardt, F., Onder, T. T., Valastyan, S., Westermann, F., Speleman, F., Vandesompele, J., & Weinberg, R. A. (2010). miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nature Cell Biology, 12(3), 247–256.

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Kishore, S., Gruber, A. R., Jedlinski, D. J., Syed, A. P., Jorjani, H., & Zavolan, M. (2013). Insights into snoRNA biogenesis and processing from PAR-CLIP of snoRNA core proteins and small RNA sequencing. Genome Biology, 14(5), R45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Choi, M. S., Shim, Y. H., Hwa, J. Y., Lee, S. K., Ro, J. Y., Kim, J. S., & Yu, E. (2003). Expression of DNA methyltransferases in multistep hepatocarcinogenesis. Human Pathology, 34(1), 11–17.

    Article  CAS  PubMed  Google Scholar 

  208. Simo-Riudalbas, L., Perez-Salvia, M., Setien, F., Villanueva, A., Moutinho, C., Martinez-Cardus, A., Moran, S., Berdasco, M., Gomez, A., Vidal, E., Soler, M., Heyn, H., Vaquero, A., de la Torre, C., Barcelo-Batllori, S., Vidal, A., Roz, L., Pastorino, U., Szakszon, K., Borck, G., Moura, C. S., Carneiro, F., Zondervan, I., Savola, S., Iwakawa, R., Kohno, T., Yokota, J., & Esteller, M. (2015). KAT6B is a tumor suppressor histone H3 lysine 23 acetyltransferase undergoing genomic loss in small cell lung cancer. Cancer Research, 75(18), 3936–3945.

    Article  CAS  PubMed  Google Scholar 

  209. Di Ruscio, A., Ebralidze, A. K., Benoukraf, T., Amabile, G., Goff, L. A., Terragni, J., Figueroa, M. E., De Figueiredo Pontes, L. L., Alberich-Jorda, M., Zhang, P., Wu, M., D'Alo, F., Melnick, A., Leone, G., Ebralidze, K. K., Pradhan, S., Rinn, J. L., & Tenen, D. G. (2013). DNMT1-interacting RNAs block gene-specific DNA methylation. Nature, 503(7476), 371–376.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Wu, Y., Liu, H., Shi, X., Yao, Y., Yang, W., & Song, Y. (2015). The long non-coding RNA HNF1A-AS1 regulates proliferation and metastasis in lung adenocarcinoma. Oncotarget, 6(11), 9160–9172.

    Article  PubMed  PubMed Central  Google Scholar 

  211. Zhan Y, Li Y, Guan B, Wang Z, Peng D, Chen Z, He A, He S, Gong Y, Li X, Zhou L (2017) Long non-coding RNA HNF1A-AS1 promotes proliferation and suppresses apoptosis of bladder cancer cells through upregulating Bcl-2. Oncotarget. 8(44), 76656–76665.

    Article  PubMed  PubMed Central  Google Scholar 

  212. Liu, Z., Wei, X., Zhang, A., Li, C., Bai, J., & Dong, J. (2016). Long non-coding RNA HNF1A-AS1 functioned as an oncogene and autophagy promoter in hepatocellular carcinoma through sponging hsa-miR-30b-5p. Biochemical and Biophysical Research Communications, 473(4), 1268–1275.

    Article  CAS  PubMed  Google Scholar 

  213. Fang C, Qiu S, Sun F, Li W, Wang Z, Yue B, Wu X, Yan D (2017) Long non-coding RNA HNF1A-AS1 mediated repression of miR-34a/SIRT1/p53 feedback loop promotes the metastatic progression of colon cancer by functioning as a competing endogenous RNA. Cancer Lett, 410, 50–62.

    Article  CAS  PubMed  Google Scholar 

  214. Fu, A., Jacobs, D. I., & Zhu, Y. (2014). Epigenome-wide analysis of piRNAs in gene-specific DNA methylation. RNA Biology, 11(10), 1301–1312.

    Article  PubMed  Google Scholar 

  215. Rajasethupathy, P., Antonov, I., Sheridan, R., Frey, S., Sander, C., Tuschl, T., & Kandel, E. R. (2012). A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity. Cell, 149(3), 693–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ghoshal, K., & Bai, S. (2007). DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc), 43(6), 395–422.

    Article  CAS  Google Scholar 

  218. Liu, X. Q., Song, W. J., Sun, T. M., Zhang, P. Z., & Wang, J. (2011). Targeted delivery of antisense inhibitor of miRNA for antiangiogenesis therapy using cRGD-functionalized nanoparticles. Molecular Pharmaceutics, 8(1), 250–259.

    Article  CAS  PubMed  Google Scholar 

  219. Love, T. M., Moffett, H. F., & Novina, C. D. (2008). Not miR-ly small RNAs: big potential for microRNAs in therapy. The Journal of Allergy and Clinical Immunology, 121(2), 309–319.

    Article  CAS  PubMed  Google Scholar 

  220. Novina, C. D., & Chabner, B. A. (2008). RNA-directed therapy: the next step in the miRNA revolution. The Oncologist, 13(1), 1–3.

    Article  CAS  PubMed  Google Scholar 

  221. Lanford, R. E., Hildebrandt-Eriksen, E. S., Petri, A., Persson, R., Lindow, M., Munk, M. E., Kauppinen, S., & Orum, H. (2010). Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science, 327(5962), 198–201.

    Article  CAS  PubMed  Google Scholar 

  222. Burnett, J. C., & Rossi, J. J. (2012). RNA-based therapeutics: current progress and future prospects. Chemistry & Biology, 19(1), 60–71.

    Article  CAS  Google Scholar 

  223. Adams, B. D., Parsons, C., & Slack, F. J. (2016). The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas. Expert Opinion on Therapeutic Targets, 20(6), 737–753.

    Article  CAS  PubMed  Google Scholar 

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Ferreira, H.J., Esteller, M. Non-coding RNAs, epigenetics, and cancer: tying it all together. Cancer Metastasis Rev 37, 55–73 (2018). https://doi.org/10.1007/s10555-017-9715-8

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