Skip to main content

Advertisement

Log in

Epigenetic dynamics in cancer stem cell dormancy

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Cancer remains one of the most challenging diseases despite significant advances of early diagnosis and therapeutic treatments. Cancerous tumors are composed of various cell types including cancer stem cells capable of self-renewal, proliferation, differentiation, and invasion of distal tumor sites. Most notably, these cells can enter a dormant cellular state that is resistant to conventional therapies. Thereby, cancer stem cells have the intrinsic potential for tumor initiation, tumor growth, metastasis, and tumor relapse after therapy. Both genetic and epigenetic alterations are attributed to the formation of multiple tumor types. This review is focused on how epigenetic dynamics involving DNA methylation and DNA oxidations are implicated in breast cancer and glioblastoma multiforme. The emergence and progression of these cancer types rely on cancer stem cells with the capacity to enter quiescence also known as a dormant cellular state, which dictates the distinct tumorigenic aggressiveness between breast cancer and glioblastomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Afifi, A. M., Saad, A. M., Al-Husseini, M. J., Elmehrath, A. O., Northfelt, D. W., & Sonbol, M. B. (2019). Causes of death after breast cancer diagnosis: a US population-based analysis. Cancer. https://doi.org/10.1002/cncr.32648.

  2. Tamimi, A. F., & Juweid, M. (2017). Epidemiology and outcome of glioblastoma. In S. De Vleeschouwer (Ed.), Glioblastoma Brisbane (AU). Chapter 8, 143–154

  3. Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L., & Rich, J. N. (2015). Cancer stem cells in glioblastoma. Genes & Development, 29(12), 1203–1217. https://doi.org/10.1101/gad.261982.115.

    Article  CAS  Google Scholar 

  4. Omuro, A., & DeAngelis, L. M. (2013). Glioblastoma and other malignant gliomas: a clinical review. JAMA, 310(17), 1842–1850. https://doi.org/10.1001/jama.2013.280319.

    Article  PubMed  CAS  Google Scholar 

  5. Kahlert, U. D., Mooney, S. M., Natsumeda, M., Steiger, H. J., & Maciaczyk, J. (2017). Targeting cancer stem-like cells in glioblastoma and colorectal cancer through metabolic pathways. International Journal of Cancer, 140(1), 10–22. https://doi.org/10.1002/ijc.30259.

    Article  PubMed  CAS  Google Scholar 

  6. Han, H. R., Park, S. A., Ahn, S., Jeun, S. S., & Ryu, C. H. (2019). Evaluation of combination treatment effect with TRAIL-secreting mesenchymal stem cells and compound C against glioblastoma. Anticancer Research, 39(12), 6635–6643. https://doi.org/10.21873/anticanres.13878.

    Article  PubMed  CAS  Google Scholar 

  7. Pantel, K., Alix-Panabieres, C., & Riethdorf, S. (2009). Cancer micrometastases. Nature Reviews. Clinical Oncology, 6(6), 339–351. https://doi.org/10.1038/nrclinonc.2009.44.

    Article  PubMed  CAS  Google Scholar 

  8. Patel, S. A., Ramkissoon, S. H., Bryan, M., Pliner, L. F., Dontu, G., Patel, P. S., et al. (2012). Delineation of breast cancer cell hierarchy identifies the subset responsible for dormancy. Scientific Reports, 2, 906–906. https://doi.org/10.1038/srep00906.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Chrun, E. S., Modolo, F., & Daniel, F. I. (2017). Histone modifications: a review about the presence of this epigenetic phenomenon in carcinogenesis. Pathology, Research and Practice, 213(11), 1329–1339. https://doi.org/10.1016/j.prp.2017.06.013.

    Article  PubMed  CAS  Google Scholar 

  10. Ben-Porath, I., Thomson, M. W., Carey, V. J., Ge, R., Bell, G. W., Regev, A., et al. (2008). An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nature Genetics, 40(5), 499–507. https://doi.org/10.1038/ng.127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Suva, M. L., Riggi, N., & Bernstein, B. E. (2013). Epigenetic reprogramming in cancer. Science, 339(6127), 1567–1570. https://doi.org/10.1126/science.1230184.

    Article  PubMed  CAS  Google Scholar 

  12. Loh, K. M., & Lim, B. (2011). A precarious balance: pluripotency factors as lineage specifiers. Cell Stem Cell, 8(4), 363–369. https://doi.org/10.1016/j.stem.2011.03.013.

    Article  PubMed  CAS  Google Scholar 

  13. Thomson, M., Liu, S. J., Zou, L. N., Smith, Z., Meissner, A., & Ramanathan, S. (2011). Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell, 145(6), 875–889. https://doi.org/10.1016/j.cell.2011.05.017.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676. https://doi.org/10.1016/j.cell.2006.07.024.

    Article  CAS  Google Scholar 

  15. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872. https://doi.org/10.1016/j.cell.2007.11.019.

    Article  PubMed  CAS  Google Scholar 

  16. Iwafuchi-Doi, M., & Zaret, K. S. (2014). Pioneer transcription factors in cell reprogramming. Genes & Development, 28(24), 2679–2692. https://doi.org/10.1101/gad.253443.114.

    Article  CAS  Google Scholar 

  17. Zhang, W., Bado, I., Wang, H., Lo, H. C., & Zhang, X. H. (2019). Bone metastasis: find your niche and fit in. Trends Cancer, 5(2), 95–110. https://doi.org/10.1016/j.trecan.2018.12.004.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rowland, B. D., Bernards, R., & Peeper, D. S. (2005). The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nature Cell Biology, 7(11), 1074–1082. https://doi.org/10.1038/ncb1314.

    Article  PubMed  CAS  Google Scholar 

  19. Utikal, J., Polo, J. M., Stadtfeld, M., Maherali, N., Kulalert, W., Walsh, R. M., et al. (2009). Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature, 460(7259), 1145–1148. https://doi.org/10.1038/nature08285.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Hanna, J., Saha, K., Pando, B., van Zon, J., Lengner, C. J., Creyghton, M. P., et al. (2009). Direct cell reprogramming is a stochastic process amenable to acceleration. Nature, 462(7273), 595–601. https://doi.org/10.1038/nature08592.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Hochedlinger, K., & Jaenisch, R. (2015). Induced pluripotency and epigenetic reprogramming. Cold Spring Harbor Perspectives in Biology, 7(12). https://doi.org/10.1101/cshperspect.a019448.

  22. De Carvalho, D. D., You, J. S., & Jones, P. A. (2010). DNA methylation and cellular reprogramming. Trends in Cell Biology, 20(10), 609–617. https://doi.org/10.1016/j.tcb.2010.08.003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Gao, Y., Chen, J., Li, K., Wu, T., Huang, B., Liu, W., et al. (2013). Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell, 12(4), 453–469. https://doi.org/10.1016/j.stem.2013.02.005.

    Article  PubMed  CAS  Google Scholar 

  24. Sardina, J. L., Collombet, S., Tian, T. V., Gomez, A., Di Stefano, B., Berenguer, C., et al. (2018). Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate. Cell Stem Cell, 23(5), 727–741.e729. https://doi.org/10.1016/j.stem.2018.08.016.

    Article  PubMed  CAS  Google Scholar 

  25. Du, Q., Wang, Z., & Schramm, V. L. (2016). Human DNMT1 transition state structure. Proceedings of the National Academy of Sciences of the United States of America, 113(11), 2916–2921. https://doi.org/10.1073/pnas.1522491113.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Okashita, N., Kumaki, Y., Ebi, K., Nishi, M., Okamoto, Y., Nakayama, M., et al. (2014). PRDM14 promotes active DNA demethylation through the ten-eleven translocation (TET)-mediated base excision repair pathway in embryonic stem cells. Development, 141(2), 269–280. https://doi.org/10.1242/dev.099622.

    Article  PubMed  CAS  Google Scholar 

  27. Bostick, M., Kim, J. K., Esteve, P. O., Clark, A., Pradhan, S., & Jacobsen, S. E. (2007). UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science, 317(5845), 1760–1764. https://doi.org/10.1126/science.1147939.

    Article  PubMed  CAS  Google Scholar 

  28. Stathopoulou, A., Chhetri, J. B., Ambrose, J. C., Esteve, P. O., Ji, L., Erdjument-Bromage, H., et al. (2017). A novel requirement for DROSHA in maintenance of mammalian CG methylation. Nucleic Acids Research, 45(16), 9398–9412. https://doi.org/10.1093/nar/gkx695.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Grosser, C., Wagner, N., Grothaus, K., & Horsthemke, B. (2015). Altering TET dioxygenase levels within physiological range affects DNA methylation dynamics of HEK293 cells. Epigenetics, 10(9), 819–833. https://doi.org/10.1080/15592294.2015.1073879.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Spruijt, C. G., Gnerlich, F., Smits, A. H., Pfaffeneder, T., Jansen, P. W., Bauer, C., et al. (2013). Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell, 152(5), 1146–1159. https://doi.org/10.1016/j.cell.2013.02.004.

    Article  PubMed  CAS  Google Scholar 

  31. Liu, L., Mao, S. Q., Ray, C., Zhang, Y., Bell, F. T., Ng, S. F., et al. (2015). Differential regulation of genomic imprinting by TET proteins in embryonic stem cells. Stem Cell Research, 15(2), 435–443. https://doi.org/10.1016/j.scr.2015.08.010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Skiles, W. M., Kester, A., Pryor, J. H., Westhusin, M. E., Golding, M. C., & Long, C. R. (2018). Oxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes. Gene Expression Patterns, 28, 1–11. https://doi.org/10.1016/j.gep.2018.01.001.

    Article  PubMed  CAS  Google Scholar 

  33. Li, X. L., Xu, J. H., Nie, J. H., & Fan, S. J. (2012). Exogenous expression of UHRF1 promotes proliferation and metastasis of breast cancer cells. Oncology Reports, 28(1), 375–383. https://doi.org/10.3892/or.2012.1792.

    Article  PubMed  CAS  Google Scholar 

  34. Unoki, M., Brunet, J., & Mousli, M. (2009). Drug discovery targeting epigenetic codes: the great potential of UHRF1, which links DNA methylation and histone modifications, as a drug target in cancers and toxoplasmosis. Biochemical Pharmacology, 78(10), 1279–1288. https://doi.org/10.1016/j.bcp.2009.05.035.

    Article  PubMed  CAS  Google Scholar 

  35. Maenohara, S., Unoki, M., Toh, H., Ohishi, H., Sharif, J., Koseki, H., et al. (2017). Role of UHRF1 in de novo DNA methylation in oocytes and maintenance methylation in preimplantation embryos. PLoS Genetics, 13(10), e1007042. https://doi.org/10.1371/journal.pgen.1007042.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Gordon, C. A., Hartono, S. R., & Chedin, F. (2013). Inactive DNMT3B splice variants modulate de novo DNA methylation. PLoS One, 8(7), e69486. https://doi.org/10.1371/journal.pone.0069486.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Noh, K. M., Wang, H., Kim, H. R., Wenderski, W., Fang, F., Li, C. H., et al. (2015). Engineering of a histone-recognition domain in Dnmt3a alters the epigenetic landscape and phenotypic features of mouse ESCs. Molecular Cell, 59(1), 89–103. https://doi.org/10.1016/j.molcel.2015.05.017.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Jeltsch, A., & Jurkowska, R. Z. (2016). Allosteric control of mammalian DNA methyltransferases - a new regulatory paradigm. Nucleic Acids Research, 44(18), 8556–8575. https://doi.org/10.1093/nar/gkw723.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Duvall-Noelle, N., Karwandyar, A., Richmond, A., & Raman, D. (2016). LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex. Oncogene, 35(9), 1122–1133. https://doi.org/10.1038/onc.2015.166.

    Article  PubMed  CAS  Google Scholar 

  40. Xue, B., Zhao, J., Feng, P., Xing, J., Wu, H., & Li, Y. (2019). Epigenetic mechanism and target therapy of UHRF1 protein complex in malignancies. Oncotargets and Therapy, 12, 549–559. https://doi.org/10.2147/ott.S192234.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Snowden, A. W., Gregory, P. D., Case, C. C., & Pabo, C. O. (2002). Gene-specific targeting of H3K9 methylation is sufficient for initiating repression in vivo. Current Biology, 12(24), 2159–2166. https://doi.org/10.1016/s0960-9822(02)01391-x.

    Article  PubMed  CAS  Google Scholar 

  42. Ko, M., An, J., Pastor, W. A., Koralov, S. B., Rajewsky, K., & Rao, A. (2015). TET proteins and 5-methylcytosine oxidation in hematological cancers. Immunological Reviews, 263(1), 6–21. https://doi.org/10.1111/imr.12239.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., et al. (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science, 324(5929), 930–935. https://doi.org/10.1126/science.1170116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Hu, X., Zhang, L., Mao, S. Q., Li, Z., Chen, J., Zhang, R. R., et al. (2014). Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. Cell Stem Cell, 14(4), 512–522. https://doi.org/10.1016/j.stem.2014.01.001.

    Article  PubMed  CAS  Google Scholar 

  45. Liu, X. S., Wu, H., Ji, X., Stelzer, Y., Wu, X., Czauderna, S., et al. (2016). Editing DNA methylation in the mammalian genome. Cell, 167(1), 233–247.e217. https://doi.org/10.1016/j.cell.2016.08.056.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Wu, M. J., Kim, M. R., Chen, Y. S., Yang, J. Y., & Chang, C. J. (2017). Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKCzeta pathway. Oncogene, 36(22), 3193–3206. https://doi.org/10.1038/onc.2016.467.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Xu, Y., Liu, S. Y., Li, J., Zhang, L., Chen, D., Zhang, J. P., et al. (2018). Real-time sensing of TET2-mediated DNA demethylation in vitro by metal-organic framework-based oxygen sensor for mechanism analysis and stem-cell behavior prediction. Analytical Chemistry, 90(15), 9330–9337. https://doi.org/10.1021/acs.analchem.8b01941.

    Article  PubMed  CAS  Google Scholar 

  48. Rasmussen, K. D., & Helin, K. (2016). Role of TET enzymes in DNA methylation, development, and cancer. Genes & Development, 30(7), 733–750. https://doi.org/10.1101/gad.276568.115.

    Article  CAS  Google Scholar 

  49. Wang, L., Zhou, Y., Xu, L., Xiao, R., Lu, X., Chen, L., et al. (2015). Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex. Nature, 523(7562), 621–625. https://doi.org/10.1038/nature14482.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Kellinger, M. W., Song, C. X., Chong, J., Lu, X. Y., He, C., & Wang, D. (2012). 5-formylcytosine and 5-carboxylcytosine reduce the rate and substrate specificity of RNA polymerase II transcription. Nature Structural & Molecular Biology, 19(8), 831–833. https://doi.org/10.1038/nsmb.2346.

    Article  CAS  Google Scholar 

  51. Globisch, D., Munzel, M., Muller, M., Michalakis, S., Wagner, M., Koch, S., et al. (2010). Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS One, 5(12), e15367. https://doi.org/10.1371/journal.pone.0015367.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Zhang, L. Y., Han, C. S., Li, P. L., & Zhang, X. C. (2016). 5-Hydroxymethylcytosine expression is associated with poor survival in cervical squamous cell carcinoma. Japanese Journal of Clinical Oncology, 46(5), 427–434. https://doi.org/10.1093/jjco/hyw002.

    Article  PubMed  Google Scholar 

  53. Zhang, P., Huang, B., Xu, X., & Sessa, W. C. (2013). Ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG), components of the demethylation pathway, are direct targets of miRNA-29a. Biochemical and Biophysical Research Communications, 437(3), 368–373. https://doi.org/10.1016/j.bbrc.2013.06.082.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Putiri, E. L., Tiedemann, R. L., Thompson, J. J., Liu, C., Ho, T., Choi, J. H., et al. (2014). Distinct and overlapping control of 5-methylcytosine and 5-hydroxymethylcytosine by the TET proteins in human cancer cells. Genome Biology, 15(6), R81. https://doi.org/10.1186/gb-2014-15-6-r81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Iyer, L. M., Abhiman, S., & Aravind, L. (2011). Natural history of eukaryotic DNA methylation systems. Progress in Molecular Biology and Translational Science, 101, 25–104. https://doi.org/10.1016/b978-0-12-387685-0.00002-0.

    Article  PubMed  CAS  Google Scholar 

  56. Iyer, L. M., Tahiliani, M., Rao, A., & Aravind, L. (2009). Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle, 8(11), 1698–1710. https://doi.org/10.4161/cc.8.11.8580.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Ko, M., An, J., Bandukwala, H. S., Chavez, L., Aijo, T., Pastor, W. A., et al. (2013). Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature, 497(7447), 122–126. https://doi.org/10.1038/nature12052.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Nguyen, A. V., Albers, C. G., & Holcombe, R. F. (2010). Differentiation of tubular and villous adenomas based on Wnt pathway-related gene expression profiles. International Journal of Molecular Medicine, 26(1), 121–125. https://doi.org/10.3892/ijmm_00000443.

    Article  PubMed  Google Scholar 

  59. Zhang, P., Rausch, C., Hastert, F. D., Boneva, B., Filatova, A., Patil, S. J., et al. (2017). Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain-dependent manner. Nucleic Acids Research, 45(12), 7118–7136. https://doi.org/10.1093/nar/gkx281.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Ludwig, A. K., Zhang, P., Hastert, F. D., Meyer, S., Rausch, C., Herce, H. D., et al. (2017). Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise. Nucleic Acids Research, 45(5), 2438–2457. https://doi.org/10.1093/nar/gkw1197.

    Article  PubMed  CAS  Google Scholar 

  61. Rausch, C., Hastert, F. D., & Cardoso, M. C. (2019). DNA modification readers and writers and their interplay. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2019.12.018.

  62. Li, L., Chen, B. F., & Chan, W. Y. (2015). An epigenetic regulator: methyl-CpG-binding domain protein 1 (MBD1). International Journal of Molecular Sciences, 16(3), 5125–5140. https://doi.org/10.3390/ijms16035125.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Wood, K. H., & Zhou, Z. (2016). Emerging molecular and biological functions of MBD2, a reader of DNA methylation. Frontiers in Genetics, 7, 93. https://doi.org/10.3389/fgene.2016.00093.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Takai, H., Masuda, K., Sato, T., Sakaguchi, Y., Suzuki, T., Suzuki, T., et al. (2014). 5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex. Cell Reports, 9(1), 48–60. https://doi.org/10.1016/j.celrep.2014.08.071.

    Article  PubMed  CAS  Google Scholar 

  65. Forloni, M., Gupta, R., Nagarajan, A., Sun, L. S., Dong, Y., Pirazzoli, V., et al. (2016). Oncogenic EGFR represses the TET1 DNA demethylase to induce silencing of tumor suppressors in cancer cells. Cell Reports, 16(2), 457–471. https://doi.org/10.1016/j.celrep.2016.05.087.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Good, C. R., Madzo, J., Patel, B., Maegawa, S., Engel, N., Jelinek, J., et al. (2017). A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer. Nucleic Acids Research, 45(14), 8269–8281. https://doi.org/10.1093/nar/gkx435.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Inoue-Choi, M., Nelson, H. H., Robien, K., Arning, E., Bottiglieri, T., Koh, W. P., et al. (2013). Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore. BMC Cancer, 13, 389. https://doi.org/10.1186/1471-2407-13-389.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Kohli, R. M., & Zhang, Y. (2013). TET enzymes, TDG and the dynamics of DNA demethylation. Nature, 502(7472), 472–479. https://doi.org/10.1038/nature12750.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Cavuoto, P., & Fenech, M. F. (2012). A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension. Cancer Treatment Reviews, 38(6), 726–736. https://doi.org/10.1016/j.ctrv.2012.01.004.

    Article  PubMed  CAS  Google Scholar 

  70. Soda, K. (2018). Polyamine metabolism and gene methylation in conjunction with one-carbon metabolism. International Journal of Molecular Sciences, 19(10). https://doi.org/10.3390/ijms19103106.

  71. Mahmoud, A. M., & Ali, M. M. (2019). Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients, 11(3). https://doi.org/10.3390/nu11030608.

  72. Gut, P., & Verdin, E. (2013). The nexus of chromatin regulation and intermediary metabolism. Nature, 502(7472), 489–498. https://doi.org/10.1038/nature12752.

    Article  PubMed  CAS  Google Scholar 

  73. Kaelin Jr., W. G., & McKnight, S. L. (2013). Influence of metabolism on epigenetics and disease. Cell, 153(1), 56–69. https://doi.org/10.1016/j.cell.2013.03.004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., et al. (2012). Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes & Development, 26(12), 1326–1338. https://doi.org/10.1101/gad.191056.112.

    Article  CAS  Google Scholar 

  75. Xu, Y., Wu, F., Tan, L., Kong, L., Xiong, L., Deng, J., et al. (2011). Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Molecular Cell, 42(4), 451–464. https://doi.org/10.1016/j.molcel.2011.04.005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Flavahan, W. A., Drier, Y., Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., et al. (2016). Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature, 529(7584), 110–114. https://doi.org/10.1038/nature16490.

    Article  PubMed  CAS  Google Scholar 

  77. Cimmino, L., Neel, B. G., & Aifantis, I. (2018). Vitamin C in stem cell reprogramming and cancer. Trends in Cell Biology, 28(9), 698–708. https://doi.org/10.1016/j.tcb.2018.04.001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Aoki, K., & Natsume, A. (2019). Overview of DNA methylation in adult diffuse gliomas. Brain Tumor Pathology, 36(2), 84–91. https://doi.org/10.1007/s10014-019-00339-w.

    Article  PubMed  CAS  Google Scholar 

  79. Bouras, E., Karakioulaki, M., Bougioukas, K. I., Aivaliotis, M., Tzimagiorgis, G., & Chourdakis, M. (2019). Gene promoter methylation and cancer: an umbrella review. Gene, 710, 333–340. https://doi.org/10.1016/j.gene.2019.06.023.

    Article  PubMed  CAS  Google Scholar 

  80. Roll, J. D., Rivenbark, A. G., Sandhu, R., Parker, J. S., Jones, W. D., Carey, L. A., et al. (2013). Dysregulation of the epigenome in triple-negative breast cancers: basal-like and claudin-low breast cancers express aberrant DNA hypermethylation. Experimental and Molecular Pathology, 95(3), 276–287. https://doi.org/10.1016/j.yexmp.2013.09.001.

    Article  PubMed  CAS  Google Scholar 

  81. Phuong, N. T., Kim, S. K., Lim, S. C., Kim, H. S., Kim, T. H., Lee, K. Y., et al. (2011). Role of PTEN promoter methylation in tamoxifen-resistant breast cancer cells. Breast Cancer Research and Treatment, 130(1), 73–83. https://doi.org/10.1007/s10549-010-1304-2.

    Article  PubMed  CAS  Google Scholar 

  82. Yang, L., Yu, S. J., Hong, Q., Yang, Y., & Shao, Z. M. (2015). Reduced expression of TET1, TET2, TET3 and TDG mRNAs are associated with poor prognosis of patients with early breast cancer. PLoS One, 10(7), e0133896. https://doi.org/10.1371/journal.pone.0133896.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Thienpont, B., Galle, E., & Lambrechts, D. (2016). TET enzymes as oxygen-dependent tumor suppressors: exciting new avenues for cancer management. Epigenomics, 8(11), 1445–1448. https://doi.org/10.2217/epi-2016-0126.

    Article  PubMed  CAS  Google Scholar 

  84. Kao, S. H., Wu, K. J., & Lee, W. H. (2016). Hypoxia, epithelial-mesenchymal transition, and TET-mediated epigenetic changes. Journal of Clinical Medicine, 5(2). https://doi.org/10.3390/jcm5020024.

  85. Adam, J., Yang, M., Soga, T., & Pollard, P. J. (2014). Rare insights into cancer biology. Oncogene, 33(20), 2547–2556. https://doi.org/10.1038/onc.2013.222.

    Article  PubMed  CAS  Google Scholar 

  86. Laukka, T., Mariani, C. J., Ihantola, T., Cao, J. Z., Hokkanen, J., Kaelin Jr., W. G., et al. (2016). Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. The Journal of Biological Chemistry, 291(8), 4256–4265. https://doi.org/10.1074/jbc.M115.688762.

    Article  PubMed  CAS  Google Scholar 

  87. Liu, Y., Jiang, W., Liu, J., Zhao, S., Xiong, J., Mao, Y., et al. (2012). IDH1 mutations inhibit multiple alpha-ketoglutarate-dependent dioxygenase activities in astroglioma. Journal of Neuro-Oncology, 109(2), 253–260. https://doi.org/10.1007/s11060-012-0914-4.

    Article  PubMed  CAS  Google Scholar 

  88. Agnihotri, S., Aldape, K. D., & Zadeh, G. (2014). Isocitrate dehydrogenase status and molecular subclasses of glioma and glioblastoma. Neurosurgical Focus, 37(6), E13. https://doi.org/10.3171/2014.9.Focus14505.

    Article  PubMed  Google Scholar 

  89. Budczies, J., & Denkert, C. (2016). Tissue-based metabolomics to analyze the breast cancer metabolome. Recent Results in Cancer Research, 207, 157–175. https://doi.org/10.1007/978-3-319-42118-6_7.

    Article  PubMed  CAS  Google Scholar 

  90. Hervouet, E., Peixoto, P., Delage-Mourroux, R., Boyer-Guittaut, M., & Cartron, P. F. (2018). Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma. Clinical Epigenetics, 10, 17. https://doi.org/10.1186/s13148-018-0450-y.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Inoue, S., Li, W. Y., Tseng, A., Beerman, I., Elia, A. J., Bendall, S. C., et al. (2016). Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell, 30(2), 337–348. https://doi.org/10.1016/j.ccell.2016.05.018.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., et al. (2009). IDH1 and IDH2 mutations in gliomas. The New England Journal of Medicine, 360(8), 765–773. https://doi.org/10.1056/NEJMoa0808710.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Muller, T., Gessi, M., Waha, A., Isselstein, L. J., Luxen, D., Freihoff, D., et al. (2012). Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas. The American Journal of Pathology, 181(2), 675–683. https://doi.org/10.1016/j.ajpath.2012.04.017.

    Article  PubMed  CAS  Google Scholar 

  94. Turcan, S., Fabius, A. W., Borodovsky, A., Pedraza, A., Brennan, C., Huse, J., et al. (2013). Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget, 4(10), 1729–1736. https://doi.org/10.18632/oncotarget.1412.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Zhou, Z., Li, H. Q., & Liu, F. (2018). DNA methyltransferase inhibitors and their therapeutic potential. Current Topics in Medicinal Chemistry, 18(28), 2448–2457. https://doi.org/10.2174/1568026619666181120150122.

    Article  PubMed  CAS  Google Scholar 

  96. Chen, A., Sceneay, J., Godde, N., Kinwel, T., Ham, S., Thompson, E. W., et al. (2018). Intermittent hypoxia induces a metastatic phenotype in breast cancer. Oncogene, 37(31), 4214–4225. https://doi.org/10.1038/s41388-018-0259-3.

    Article  PubMed  CAS  Google Scholar 

  97. Flavahan, W. A., Gaskell, E., & Bernstein, B. E. (2017). Epigenetic plasticity and the hallmarks of cancer. Science, 357(6348). https://doi.org/10.1126/science.aal2380.

  98. Prasad, P., Mittal, S. A., Chongtham, J., Mohanty, S., & Srivastava, T. (2017). Hypoxia-mediated epigenetic regulation of stemness in brain tumor cells. Stem Cells, 35(6), 1468–1478. https://doi.org/10.1002/stem.2621.

    Article  PubMed  CAS  Google Scholar 

  99. Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., et al. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature, 367(6464), 645–648. https://doi.org/10.1038/367645a0.

    Article  PubMed  CAS  Google Scholar 

  100. Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–111. https://doi.org/10.1038/35102167.

    Article  PubMed  CAS  Google Scholar 

  101. Giordano, A., Gao, H., Cohen, E. N., Anfossi, S., Khoury, J., Hess, K., et al. (2013). Clinical relevance of cancer stem cells in bone marrow of early breast cancer patients. Annals of oncology : official journal of the European Society for Medical Oncology, 24(10), 2515–2521. https://doi.org/10.1093/annonc/mdt223.

    Article  CAS  Google Scholar 

  102. Bu, Y., & Cao, D. (2012). The origin of cancer stem cells. Frontiers in Bioscience (Scholar Edition), 4, 819–830. https://doi.org/10.2741/s302.

    Article  Google Scholar 

  103. Prieto-Vila, M., Takahashi, R.-U., Usuba, W., Kohama, I., & Ochiya, T. (2017). Drug resistance driven by cancer stem cells and their niche. International Journal of Molecular Sciences, 18(12). https://doi.org/10.3390/ijms18122574.

  104. Lobo, N. A., Shimono, Y., Qian, D., & Clarke, M. F. (2007). The biology of cancer stem cells. Annual Review of Cell and Developmental Biology, 23(1), 675–699. https://doi.org/10.1146/annurev.cellbio.22.010305.104154.

    Article  PubMed  CAS  Google Scholar 

  105. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M.F. F. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA, 100(7), 3983–3988

  106. Hwang-Verslues, W. W., Kuo, W.-H., Chang, P.-H., Pan, C.-C., Wang, H.-H., Tsai, S.-T., et al. Multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem cell markers multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem. Cell Markers. PLoS ONE, 4(12), 8377–8377. https://doi.org/10.1371/journal.pone.0008377.

  107. Figueiredo, E., Zaghloul, K., Zhang, Y., Tan, S. T., Bradshaw, A., Wickremsekera, A., et al. (2016). Cancer stem cell hierarchy in glioblastoma multiforme. 3, 2, doi:https://doi.org/10.3389/fsurg.2016.00021.

  108. Bliss, S. A., Sinha, G., Sandiford, O. A., Williams, L. M., Engelberth, D. J., Guiro, K., et al. (2016). Mesenchymal stem cell–derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Research, 76(19), 5832–5844. https://doi.org/10.1158/0008-5472.CAN-16-1092.

    Article  PubMed  CAS  Google Scholar 

  109. Mani, S. A., Guo, W., Liao, M.-J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704–715. https://doi.org/10.1016/j.cell.2008.03.027.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Sell, S. (2004). Stem cell origin of cancer and differentiation therapy. Critical Reviews in Oncology/Hematology, 51(1), 1–28. https://doi.org/10.1016/J.CRITREVONC.2004.04.007.

    Article  PubMed  Google Scholar 

  111. Wicha, M. S., Liu, S., & Dontu, G. (2006). Cancer stem cells: an old idea-A paradigm shift. Cancer Research, 66(4), 1883–1890. https://doi.org/10.1158/0008-5472.CAN-05-3153.

    Article  PubMed  CAS  Google Scholar 

  112. Marsden, C. G., Wright, M. J., Carrier, L., Moroz, K., & Rowan, B. G. (2012). Disseminated breast cancer cells acquire a highly malignant and aggressive metastatic phenotype during metastatic latency in the bone. PLoS One, 7(11), e47587–e47587. https://doi.org/10.1371/journal.pone.0047587.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Shiozawa, Y., & Taichman, R. S. (2012). Cancer stem cells and the bone marrow microenvironment. Bonekey Reports, 2012(1). https://doi.org/10.1038/bonekey.2012.48.

  114. Birbrair, A., & Frenette, P. S. (2016). Niche heterogeneity in the bone marrow. Annals of the New York Academy of Sciences, 1370(1), 82–96. https://doi.org/10.1111/nyas.13016.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Morrison, S. J., & Scadden, D. T. (2014). The bone marrow niche for haematopoietic stem cells. Nature, 505(7483), 327–334. https://doi.org/10.1038/nature12984.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Yu, V. W., & Scadden, D. T. (2016). Hematopoietic stem cell and its bone marrow niche. Current Topics in Developmental Biology, 118, 21–44. https://doi.org/10.1016/bs.ctdb.2016.01.009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Guerra, D. A. P., Paiva, A. E., Sena, I. F. G., Azevedo, P. O., Batista Jr., M. L., Mintz, A., et al. (2018). Adipocytes role in the bone marrow niche. Cytometry. Part A, 93(2), 167–171. https://doi.org/10.1002/cyto.a.23301.

    Article  Google Scholar 

  118. Rameshwar, P. (2010). Breast cancer cell dormancy in bone marrow: potential therapeutic targets within the marrow microenvironment. Expert Review of Anticancer Therapy, 10(2), 129–132. https://doi.org/10.1586/era.10.3.

    Article  PubMed  CAS  Google Scholar 

  119. Eltoukhy, H. S., Sinha, G., Moore, C. A., Gergues, M., & Rameshwar, P. (2018). Secretome within the bone marrow microenvironment: a basis for mesenchymal stem cell treatment and role in cancer dormancy. Biochimie, 155, 92–103. https://doi.org/10.1016/j.biochi.2018.05.018.

    Article  PubMed  CAS  Google Scholar 

  120. Ridge, S. M., Sullivan, F. J., & Glynn, S. A. (2017). Mesenchymal stem cells: key players in cancer progression. Molecular Cancer, 16(1), 31. https://doi.org/10.1186/s12943-017-0597-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Ruivo, C. F., Adem, B., Silva, M., & Melo, S. A. (2017). The biology of cancer exosomes: insights and new perspectives. Cancer Research, 77(23), 6480–6488. https://doi.org/10.1158/0008-5472.CAN-17-0994.

    Article  PubMed  CAS  Google Scholar 

  122. Walker, N. D., Elias, M., Guiro, K., Bhatia, R., Greco, S. J., Bryan, M., et al. (2019). Exosomes from differentially activated macrophages influence dormancy or resurgence of breast cancer cells within bone marrow stroma. Cell Death & Disease, 10(2), 59. https://doi.org/10.1038/s41419-019-1304-z.

    Article  CAS  Google Scholar 

  123. Wu, J. I., & Wang, L. H. (2019). Emerging roles of gap junction proteins connexins in cancer metastasis, chemoresistance and clinical application. Journal of Biomedical Science, 26(1), 8. https://doi.org/10.1186/s12929-019-0497-x.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Zefferino, R., Piccoli, C., Gioia, S. D., Capitanio, N., & Conese, M. (2019). Gap junction intercellular communication in the carcinogenesis hallmarks: is this a phenomenon or epiphenomenon? Cells, 8(8). https://doi.org/10.3390/cells8080896.

  125. Sinyuk, M., Mulkearns-Hubert, E. E., Reizes, O., & Lathia, J. (2018). Cancer connectors: connexins, gap junctions, and communication. Frontiers in Oncology, 8, 646. https://doi.org/10.3389/fonc.2018.00646.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Busby, M., Hallett, M. T., & Plante, I. (2018). The complex subtype-dependent role of connexin 43 (GJA1) in breast cancer. International Journal of Molecular Sciences, 19(3). https://doi.org/10.3390/ijms19030693.

  127. Oliveira, R., Christov, C., Guillamo, J. S., de Bouard, S., Palfi, S., Venance, L., et al. (2005). Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas. BMC Cell Biology, 6(1), 7. https://doi.org/10.1186/1471-2121-6-7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Munoz, J. L., Bliss, S. A., Greco, S. J., Ramkissoon, S. H., Ligon, K. L., & Rameshwar, P. (2013). Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Molecular Therapy--Nucleic Acids, 2, e126. https://doi.org/10.1038/mtna.2013.60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Park, J. M., Munoz, J. L., Won, B. W., Bliss, S. A., Greco, S. J., Patel, S. A., et al. (2013). Exogenous CXCL12 activates protein kinase C to phosphorylate connexin 43 for gap junctional intercellular communication among confluent breast cancer cells. Cancer Letters, 331(1), 84–91. https://doi.org/10.1016/j.canlet.2012.12.007.

    Article  PubMed  CAS  Google Scholar 

  130. Poddar, S., Kesharwani, D., & Datta, M. (2017). Interplay between the miRNome and the epigenetic machinery: implications in health and disease. Journal of Cellular Physiology, 232(11), 2938–2945. https://doi.org/10.1002/jcp.25819.

    Article  PubMed  CAS  Google Scholar 

  131. Piletic, K., & Kunej, T. (2016). MicroRNA epigenetic signatures in human disease. Archives of Toxicology, 90(10), 2405–2419. https://doi.org/10.1007/s00204-016-1815-7.

    Article  PubMed  CAS  Google Scholar 

  132. Tu, J., Ng, S. H., Luk, A. C., Liao, J., Jiang, X., Feng, B., et al. (2015). MicroRNA-29b/Tet1 regulatory axis epigenetically modulates mesendoderm differentiation in mouse embryonic stem cells. Nucleic Acids Research, 43(16), 7805–7822. https://doi.org/10.1093/nar/gkv653.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Iwama, H., Kato, K., Imachi, H., Murao, K., & Masaki, T. (2018). Human microRNAs preferentially target genes with intermediate levels of expression and its formation by mammalian evolution. PLoS One, 13(5), e0198142. https://doi.org/10.1371/journal.pone.0198142.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Liu, X., Chen, X., Yu, X., Tao, Y., Bode, A. M., Dong, Z., et al. (2013). Regulation of microRNAs by epigenetics and their interplay involved in cancer. Journal of Experimental & Clinical Cancer Research, 32, 96. https://doi.org/10.1186/1756-9966-32-96.

    Article  CAS  Google Scholar 

  135. Daniunaite, K., Dubikaityte, M., Gibas, P., Bakavicius, A., Rimantas Lazutka, J., Ulys, A., et al. (2017). Clinical significance of miRNA host gene promoter methylation in prostate cancer. Human Molecular Genetics, 26(13), 2451–2461. https://doi.org/10.1093/hmg/ddx138.

    Article  PubMed  CAS  Google Scholar 

  136. Pathania, R. a. R. S. a. E. S. a. P. R. a. Y. P. a. C. S. a. V.-K. R. a. A. P. a. G.-P. J. P. a. S. (2015). DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nature Communications, 6(1), 6910. https://doi.org/10.1038/ncomms7910.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Oltra, S. S., Peña-Chilet, M., Flower, K., Martinez, M. T., Alonso, E., Burgues, O., et al. (2019). Acceleration in the DNA methylation age in breast cancer tumours from very young women. Scic Rep, 9(1). https://doi.org/10.1038/s41598-019-51457-6.

  138. El Helou, R., Wicinski, J., Guille, A., Adélaïde, J., Finetti, P., Bertucci, F., et al. (2014). Brief reports: a distinct DNA methylation signature defines breast cancer stem cells and predicts cancer outcome. Stem Cells, 32(11), 3031–3036. https://doi.org/10.1002/stem.1792.

    Article  PubMed  CAS  Google Scholar 

  139. Taube, J. H., Malouf, G. G., Lu, E., Sphyris, N., Vijay, V., Ramachandran, P. P., et al. (2013). Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties. Scientific Reports, 3, 2687. https://doi.org/10.1038/srep02687.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Neves, R., Scheel, C., Weinhold, S., Honisch, E., Iwaniuk, K. M., Trompeter, H. I., et al. (2010). Role of DNA methylation in miR-200c/141 cluster silencing in invasive breast cancer cells. BMC Research Notes, 3, 219. https://doi.org/10.1186/1756-0500-3-219.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Nass, S. J., Herman, J. G., Gabrielson, E., Iversen, P. W., Parl, F. F., Davidson, N. E., et al. (2000). Aberrant methylation of the estrogen receptor and E-cadherin 5′ CpG islands increases with malignant progression in human breast cancer. Cancer Research, 60(16), 4346–4348.

    PubMed  CAS  Google Scholar 

  142. Joo, J. E., Dowty, J. G., Milne, R. L., Wong, E. M., Dugue, P. A., English, D., et al. (2018). Heritable DNA methylation marks associated with susceptibility to breast cancer. Nature Communications, 9(1), 867. https://doi.org/10.1038/s41467-018-03058-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Fleischer, T., Tekpli, X., Mathelier, A., Wang, S., Nebdal, D., Dhakal, H. P., et al. (2017). DNA methylation at enhancers identifies distinct breast cancer lineages. Nature Communications, 8, 1379. https://doi.org/10.1038/s41467-017-00510-x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Hernandez-Vargas, H., Ouzounova, M., Le Calvez-Kelm, F., Lambert, M. P., McKay-Chopin, S., Tavtigian, S. V., et al. (2011). Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. Epigenetics, 6(4), 428–439. https://doi.org/10.4161/epi.6.4.14515.

    Article  PubMed  CAS  Google Scholar 

  145. Chimonidou, M., Strati, A., Tzitzira, A., Sotiropoulou, G., Malamos, N., Georgoulias, V., et al. (2011). DNA methylation of tumor suppressor and metastasis suppressor genes in circulating tumor cells. Clinical Chemistry, 57(8), 1169–1177. https://doi.org/10.1373/clinchem.2011.165902.

    Article  PubMed  CAS  Google Scholar 

  146. Darvin, P., Sasidharan Nair, V., & Elkord, E. (2019). PD-L1 expression in human breast cancer stem cells is epigenetically regulated through posttranslational histone modifications. Journal of Oncology, 2019, 3958908. https://doi.org/10.1155/2019/3958908.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Rankin, E. B., & Giaccia, A. J. (2008). The role of hypoxia-inducible factors in tumorigenesis. Cell Death and Differentiation, 15(4), 678–685. https://doi.org/10.1038/cdd.2008.21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Guo, C., Chen, L. H., Huang, Y., Chang, C. C., Wang, P., Pirozzi, C. J., et al. (2013). KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation. Oncotarget, 4(11), 2144–2153. https://doi.org/10.18632/oncotarget.1555.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Wang, L., Ozark, P. A., Smith, E. R., Zhao, Z., Marshall, S. A., Rendleman, E. J., et al. (2018). TET2 coactivates gene expression through demethylation of enhancers. Science Advances, 4(11), eaau6986. https://doi.org/10.1126/sciadv.aau6986.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Chen, J. Y., Luo, C. W., Lai, Y. S., Wu, C. C., & Hung, W. C. (2017). Lysine demethylase KDM2A inhibits TET2 to promote DNA methylation and silencing of tumor suppressor genes in breast cancer. Oncogenesis, 6(8), e369. https://doi.org/10.1038/oncsis.2017.71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Yu, Y., Qi, J., Xiong, J., Jiang, L., Cui, D., He, J., et al. (2019). Epigenetic co-deregulation of EZH2/TET1 is a senescence-countering, actionable vulnerability in triple-negative breast cancer. Theranostics, 9(3), 761–777. https://doi.org/10.7150/thno.29520.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Wu, M. Z., Chen, S. F., Nieh, S., Benner, C., Ger, L. P., Jan, C. I., et al. (2015). Hypoxia drives breast tumor malignancy through a TET-TNFalpha-p38-MAPK signaling axis. Cancer Research, 75(18), 3912–3924. https://doi.org/10.1158/0008-5472.CAN-14-3208.

    Article  PubMed  CAS  Google Scholar 

  153. Thienpont, B., Steinbacher, J., Zhao, H., D’Anna, F., Kuchnio, A., Ploumakis, A., et al. (2016). Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature, 537(7618), 63–68. https://doi.org/10.1038/nature19081.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Ryan Good, C., Panjarian, S., Kelly, A. D., Madzo, J., Patel, B., Jelinek, J., et al. (2018). Genome and epigenome TET1-mediated hypomethylation activates oncogenic signaling in triple-negative. Breast Cancer. https://doi.org/10.1158/0008-5472.CAN-17-2082.

  155. Hsu, C. H., Peng, K. L., Kang, M. L., Chen, Y. R., Yang, Y. C., Tsai, C. H., et al. (2012). TET1 suppresses cancer invasion by activating the tissue inhibitors of metalloproteinases. Cell Reports, 2(3), 568–579. https://doi.org/10.1016/j.celrep.2012.08.030.

    Article  PubMed  CAS  Google Scholar 

  156. Collignon, E., Canale, A., Al Wardi, C., Bizet, M., Calonne, E., Dedeurwaerder, S., et al. (2018). Immunity drives TET1 regulation in cancer through NF-kappaB. Science Advances, 4(6), eaap7309. https://doi.org/10.1126/sciadv.aap7309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Sant, D. W., Mustafi, S., Gustafson, C. B., Chen, J., Slingerland, J. M., & Wang, G. (2018). Vitamin C promotes apoptosis in breast cancer cells by increasing TRAIL expression. Scientific Reports, 8(1), 5306. https://doi.org/10.1038/s41598-018-23714-7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Klughammer, J., Kiesel, B., Roetzer, T., Fortelny, N., Nemc, A., Nenning, K. H., et al. (2018). The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space. Nature Medicine, 24(10), 1611–1624. https://doi.org/10.1038/s41591-018-0156-x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Lee, E. J., Rath, P., Liu, J., Ryu, D., Pei, L., Noonepalle, S. K., et al. (2015). Identification of global DNA methylation signatures in glioblastoma-derived cancer stem cells. Journal of Genetics and Genomics, 42(7), 355–371. https://doi.org/10.1016/j.jgg.2015.06.003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Bulstrode, H., Johnstone, E., Marques-Torrejon, M. A., Ferguson, K. M., Bressan, R. B., Blin, C., et al. (2017). Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators. Genes & Development, 31(8), 757–773. https://doi.org/10.1101/gad.293027.116.

    Article  CAS  Google Scholar 

  161. Gopisetty, G., Xu, J., Sampath, D., Colman, H., & Puduvalli, V. K. (2013). Epigenetic regulation of CD133/PROM1 expression in glioma stem cells by Sp1/myc and promoter methylation. Oncogene, 32(26), 3119–3129. https://doi.org/10.1038/onc.2012.331.

    Article  PubMed  CAS  Google Scholar 

  162. Iwadate, Y., Suganami, A., Tamura, Y., Matsutani, T., Hirono, S., Shinozaki, N., et al. (2017). The pluripotent stem-cell marker alkaline phosphatase is highly expressed in refractory glioblastoma with DNA hypomethylation. Neurosurgery, 80(2), 248–256. https://doi.org/10.1093/neuros/nyw026.

    Article  PubMed  Google Scholar 

  163. Zhou, D., Wan, Y., Xie, D., Wang, Y., Wei, J., Yan, Q., et al. (2015). DNMT1 mediates chemosensitivity by reducing methylation of miRNA-20a promoter in glioma cells. Experimental & Molecular Medicine, 47, e182. https://doi.org/10.1038/emm.2015.57.

    Article  CAS  Google Scholar 

  164. Ning, X., Shi, Z., Liu, X., Zhang, A., Han, L., Jiang, K., et al. (2015). DNMT1 and EZH2 mediated methylation silences the microRNA-200b/a/429 gene and promotes tumor progression. Cancer Letters, 359(2), 198–205. https://doi.org/10.1016/j.canlet.2015.01.005.

    Article  PubMed  CAS  Google Scholar 

  165. Hervouet, E., Vallette, F. M., & Cartron, P. F. (2010). Impact of the DNA methyltransferases expression on the methylation status of apoptosis-associated genes in glioblastoma multiforme. Cell Death & Disease, 1, e8. https://doi.org/10.1038/cddis.2009.7.

    Article  CAS  Google Scholar 

  166. Gu, X., Gong, H., Shen, L., & Gu, Q. (2018). MicroRNA-129-5p inhibits human glioma cell proliferation and induces cell cycle arrest by directly targeting DNMT3A. American Journal of Translational Research, 10(9), 2834–2847.

    PubMed  PubMed Central  CAS  Google Scholar 

  167. Sun, J., Tian, X., Zhang, J., Huang, Y., Lin, X., Chen, L., et al. (2017). Regulation of human glioma cell apoptosis and invasion by miR-152-3p through targeting DNMT1 and regulating NF2 : MiR-152-3p regulate glioma cell apoptosis and invasion. Journal of Experimental & Clinical Cancer Research, 36(1), 100. https://doi.org/10.1186/s13046-017-0567-4.

    Article  CAS  Google Scholar 

  168. Izumikawa, K., Ishikawa, H., Simpson, R. J., & Takahashi, N. (2018). Modulating the expression of Chtop, a versatile regulator of gene-specific transcription and mRNA export. RNA Biology, 15(7), 849–855. https://doi.org/10.1080/15476286.2018.1465795.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Johnson, K. C., Houseman, E. A., King, J. E., von Herrmann, K. M., Fadul, C. E., & Christensen, B. C. (2016). 5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients. Nature Communications, 7, 13177. https://doi.org/10.1038/ncomms13177.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Carella, A., Tejedor, J. R., García, M. G., Urdinguio, R. G., Bayón, G. F., Sierra, M., et al. (2020). Epigenetic downregulation of TET3 reduces genome-wide 5hmC levels and promotes glioblastoma tumorigenesis. International Journal of Cancer, 146(2), 373–387. https://doi.org/10.1002/ijc.32520.

    Article  PubMed  CAS  Google Scholar 

  171. Qu, Q., Sun, G., Li, W., Yang, S., Ye, P., Zhao, C., et al. (2010). Orphan nuclear receptor TLX activates Wnt/Β-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nature Cell Biology, 12(1), 31–40. https://doi.org/10.1038/ncb2001.

    Article  PubMed  CAS  Google Scholar 

  172. Cui, Q., Yang, S., Ye, P., Tian, E., Sun, G., Zhou, J., et al. (2016). Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis. Nature Communications, 7, 10637. https://doi.org/10.1038/ncomms10637.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Zhou, D., Alver, B. M., Li, S., Hlady, R. A., Thompson, J. J., Schroeder, M. A., et al. (2018). Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues. Genome Biology, 19(1), 43–43. https://doi.org/10.1186/s13059-018-1420-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Puig, I., Tenbaum, S. P., Chicote, I., Arques, O., Martinez-Quintanilla, J., Cuesta-Borras, E., et al. (2018). TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence. The Journal of Clinical Investigation, 128(9), 3887–3905. https://doi.org/10.1172/jci96393.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Garcia, M. G., Carella, A., Urdinguio, R. G., Bayon, G. F., Lopez, V., Tejedor, J. R., et al. (2018). Epigenetic dysregulation of TET2 in human glioblastoma. Oncotarget, 9(40), 25922–25934. https://doi.org/10.18632/oncotarget.25406.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Huang, Y., Chavez, L., Chang, X., Wang, X., Pastor, W. A., Kang, J., et al. (2014). Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 111(4), 1361–1366. https://doi.org/10.1073/pnas.1322921111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Xu, Y., Chao, L., Wang, J., & Sun, Y. (2017). miRNA-148a regulates the expression of the estrogen receptor through DNMT1-mediated DNA methylation in breast cancer cells. Oncology Letters, 14(4), 4736–4740. https://doi.org/10.3892/ol.2017.6803.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Cho, J. H., Dimri, M., & Dimri, G. P. (2015). MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence. The Journal of Biological Chemistry, 290(16), 10555–10567. https://doi.org/10.1074/jbc.M114.624361.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Song, J., Jin, E. H., Kim, D., Kim, K. Y., Chun, C. H., & Jin, E. J. (2015). MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis. BBA Clinical, 3, 79–89. https://doi.org/10.1016/j.bbacli.2014.11.009.

    Article  PubMed  Google Scholar 

  180. Jiang, S. (2019). MicroRNA Let-7adf in Tet regulation. Aging, 11(14), 4772–4773. https://doi.org/10.18632/aging.102101.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Fu, X., Jin, L., Wang, X., Luo, A., Hu, J., Zheng, X., et al. (2013). MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation. Proceedings of the National Academy of Sciences of the United States of America, 110(44), 17892–17897. https://doi.org/10.1073/pnas.1317397110.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Cheng, J., Guo, S., Chen, S., Mastriano, S. J., Liu, C., D’Alessio, A. C., et al. (2013). An extensive network of TET2-targeting microRNAs regulates malignant hematopoiesis. Cell Reports, 5(2), 471–481. https://doi.org/10.1016/j.celrep.2013.08.050.

    Article  PubMed  CAS  Google Scholar 

  183. Yang, H., Li, Q., Zhao, W., Yuan, D., Zhao, H., & Zhou, Y. (2014). miR-329 suppresses the growth and motility of neuroblastoma by targeting KDM1A. FEBS Letters, 588(1), 192–197. https://doi.org/10.1016/j.febslet.2013.11.036.

    Article  PubMed  CAS  Google Scholar 

  184. Nilsson, E. M., Laursen, K. B., Whitchurch, J., McWilliam, A., Odum, N., Persson, J. L., et al. (2015). MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators. Oncotarget, 6(34), 35710–35725. https://doi.org/10.18632/oncotarget.5958.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Bao, J., Zou, J. H., Li, C. Y., & Zheng, G. Q. (2016). miR-194 inhibits gastric cancer cell proliferation and tumorigenesis by targeting KDM5B. European Review for Medical and Pharmacological Sciences, 20(21), 4487–4493.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jean-Pierre Etchegaray or Pranela Rameshwar.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ferrer, A.I., Trinidad, J.R., Sandiford, O. et al. Epigenetic dynamics in cancer stem cell dormancy. Cancer Metastasis Rev 39, 721–738 (2020). https://doi.org/10.1007/s10555-020-09882-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-020-09882-x

Keywords

Navigation