Abstract
Cancer cells and tissues exhibit genome wide hypomethylation and regional hypermethylation. CpG-methylation of DNA (MeCpG-DNA) is defined as the formation of a C–C covalent bond between the 5′-C of cytosine and the –CH3 group of S-adenosylmethionine. Removal of the sole –CH3 group from the methylated cytosine of DNA is one of the many ways of DNA-demethylation, which contributes to activation of transcription. The mechanism of demethylation, the candidate enzyme(s) exhibiting direct demethylase activity and associated cofactors are not firmly established. Genome-wide hypomethylation can be obtained in several ways by inactivation of DNMT enzyme activity, including covalent trapping of DNMT by cytosine base analogues. Removal of methyl layer could also be occurred by excision of the 5-methyl cytosine base by DNA glycosylases. The importance of truly chemically defined direct demethylation of intact DNA in regulation of gene expression, development, cell differentiation and transformation are discussed in this contribution.
Similar content being viewed by others
References
Reik, W., Dean, W., & Walter, J. (2001). Epigenetic reprogramming in mammalian development. Science, 293, 1089–1093.
Surani, M. A. (2002). Immaculate misconception—Genetics. Nature, 416, 491–493.
Judson, H., Hayward, B. E., Sheridan, E., & Bonthron, D. T. (2002). A global disorder of imprinting in the human female germ line. Nature, 416, 539–542.
Hata, K., Okano, M., Lei, H., & Li, E. (2002). Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development, 129, 1983–1993.
Bourc’his, D., Xu, G. L., Lin, C. S., Bollman, B., & Bestor, T. H. (2001). Dnmt3L and the establishment of maternal genomic imprints. Science, 294, 2536–2539.
McLay, D. W., & Clarke, H.J. (2003). Remodelling the paternal chromatin at fertilization in mammals. Reproduction, 125, 625–633.
Haaf, T. (2006). Methylation dynamics in the early mammalian embryo: implications of genome reprogramming defects for development. Current Topics in Microbiology and Immunology, 310, 13–22.
Hove, J. R., Koster, R. W., Forouhar, A. S., Acevedo-Bolton, G., Fraser, S. E., & Gharib, M. (2003). Intracardiac fluid forces are essential epigenetic factor for embryonic cardiogenesis. Nature, 421, 172–177.
Patra, S. K. (2008). Dissecting lipid raft facilitated cell signaling pathways in cancer. Biochimica et Biophysica Acta. doi:10.1016/j.bbcan2007.11.002.
Konner, M. (2002). Development: Weaving life’s pattern. Nature, 418, 279.
Waddington, C. H. (1957). The strategy of the genes: A discussion of some aspects of theoretical biology. New York: Macmillan.
Hotchkiss, R. D. (1948). The quantitative separation of purines, pyrimidines and nucleosides by paper chromatography. Journal of Biological Chemistry, 175, 315–332.
Smith, S. S. (2000). Gilbert’s conjecture: The search for DNA (Cytosine-5) demethylase and the emergence of new functions for eukaryotic DNA (Cytosine-5) methyltransferases. Journal of Molecular Biology, 302, 1–7.
Bestor, T. H. (2000). The DNA methyltransferases of mammals. Human Molecular Genetics, 9, 2395–2402.
Patra, S. K., Patra, A., Zhao, H., & Dahiya, R. (2002). DNA methyltransferase and demethylase in human prostate cancer. Molecular Carcinogenesis, 33, 163–171.
Patra, S. K., Patra, A., Zhao, H., Carroll, P., & Dahiya, R. (2003). Methyl-CpG-DNA binding proteins in human prostate cancer: expression of CXXC sequence containing MBD1 and repression of MBD2 and MeCP2. Biochemical and Biophysical Research Communications, 302, 759–766.
Patra, S. K., Patra, A., & Dahiya, R. (2001). Histone deacetylase and DNA methyltransferase in human prostate cancer. Biochemical and Biophysical Research Communications, 287, 705–713.
Bhattacharya, S. K., Ramchandani, S., Cervoni, N., & Szyf, M. (1999). A mammalian protein with specific demethylase activity for mCpG DNA. Nature, 397, 579–783.
Ramchandani, S., Bhattacharya, S. K., Cervoni, N., & Szyf, M. (1999). DNA methylation is a reversible biological signal. Proceedings of the National Academy of Sciences of the USA, 96, 6107–6112.
Goel, A., Mathupala, S. P., & Pedersen, P. L. (2003). Glucose metabolism in cancer: Evidence that demethylation events play a role in activating type II hexokinase gene expression. Journal of Biological Chemistry, 278, 15333–15340.
Cervoni, N., & Szyf, M. (2001). Demethylase activity is directed by histone acetylation. Journal of Biological Chemistry, 276, 40778–40787.
Cervoni, N., Bhattacharya, S. K., & Szyf, M. (1999). DNA demethylase is a processive enzyme. Journal of Biological Chemistry, 274, 8363–8366.
Guo, Y., Pakneshan, P., Gladu, J., Slak, A., Szyf, M., & Rabbani, S. A. (2002). Regulation of DNA methylation in human breast cancer—Effect on the urokinase-type plasminogen activator gene production and tumor invasion. Journal of Biological Chemistry, 277, 41571–41579.
Wade, P. A., Gregonne, A., Jones, P. L., Ballester, E., Aubry, F., & Wolf, A. P. (1999). Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genetics, 23, 61–66.
Ng, H. H., Zhang, Y., Hendrich, B., Johnson, C. A., Turner, B. M., Erdjument-Bromage, H., Tempst, P., Reinberg, D., & Bird, A. (1999). MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genetics, 23, 58–61.
Fujita, H., Fuji, R., Aratani, S., Amano, T., Fukamizu, A., & Nakajima, T. (2003). Antithetic effects of MBD2a on gene regulation. Molecular and Cellular Biology, 23, 2645–2657.
Kress, C., Thomassin, H., & Grange, T. (2006). Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks. Proceedings of the National Academy of Sciences of the USA, 103, 11112–11117.
Barreto, G., Schafer, A., Marhold, J., Stach, D., Swaminathan, S. K., Handa, V., et al. (2007). Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature, 445, 671–675.
Thomassin, H., Flavin, M., Espinas, M.-L., & Grange, T. (2001). Glucocorticoid-induced DNA demethylation and gene memory during development. EMBO Journal, 20, 1974–1983.
Kress, C., Thomassin, H., & Grange, T. (2001). Local DNA demethylation in vertebrates: how could it be performed and targeted? FEBS Letters, 494, 135–140.
Jost, J.-P., Thiry, S., & Sigman, M. (2002). 5-Methyldeoxycytidine monophosphate deaminase and 5-methylcytidyl-DNA deaminase activities are present in human mature sperm cells. FEBS Letters, 519, 128–134.
Surani, M. A. (2001). Reprogramming of genome function through epigenetic inheritance. Nature, 414, 122–128.
Patra, S. K., & Bettuzzi, S. (2007). Epigenetic DNA methylation regulation of genes coding for lipid raft-associated components: A role for raft proteins in cell transformation and cancer progression (Review). Oncology Reports, 17, 1279–1290.
Jones, P. A., & Baylin, S. B. (2002). The fundamental role of epigenetic events in cancer. Nature Reviews (Genetics), 3, 416–428.
Hendrich, B., & Bird, A. (1998). Identification and characterization of a family of mammalian methyl-CpG binding proteins. Molecular and Cellular Biology, 18, 6538–6547.
Tan, C. P., & Nakielny, S. (2006). Control of the DNA methylation system component MBD2 by protein arginine methylation. Molecular and Cellular Biology, 26, 7224–7235.
Wade, P. A. (2001). Methyl CpG-binding proteins and transcriptional repression. BioEssays, 23, 1131–1137.
Lee, J.-H., Voo, K. S., & Skalnik, D. G. (2001). Identification and characterization of the DNA binding domain of CpG-binding protein. Journal of Biological Chemistry, 276, 44669–44676.
Feng, Q., & Zhang, Y. (2001). The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. Genes & Development, 15, 827–832.
Lopez-Serra, L., Ballestar, E., Fraga, M. F., Alaminos, M., Setien, F., & Esteller, M. (2006). A profile of Methyl-CpG binding domain protein occupancy of hypermethylated promoter CpG-islands of tumor suppressor genes in human cancer. Cancer Research, 66, 8342–8346.
Lembo, F., Pero, R., Angrisano, T., Vitiello, C., Iuliano, R., Bruni, C. B., et al. (2003). MBDin, a novel MBD2-interacting protein, relieves MBD2 repression potential and reactivates transcription from methylated promoters. Molecular and Cellular Biology, 23, 1656–1665.
Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J. R., Cole, P. A., et al. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 119, 941–953.
Kubicek, S., & Jenuwein, T. (2004). A crack in histone lysine methylation. Cell, 119, 903–906.
Ehrlich, M. (2006). Cancer-linked DNA hypomethylation and its relationship to hypermethylation. Current Topics in Microbiology and Immunology, 310, 251–274.
Rodriguez, J., Frigola, J., Vendrell, E., Risques, R. A., Fraga, M. F., Morales, C., et al. (2006). Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Research, 66, 8462–9468.
Bruniquel, D., & Schwartz, R. H. (2003). Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nature Immunology, 4, 235–240.
Santos, F., Hendrich, B., Reik, W., & Dean, W. (2002). Dynamic reprogramming of DNA methylation in the early mouse embryo. Developments in Biologicals, 241, 172–182.
Li, E., Bestor, T. H., & Jaenisch, R. (1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell, 69, 915–926.
Lewin, B. (1995). GENE-V. In B.Lewin (Ed.) Systems that safeguard DNA (pp. 605–629). Oxford, NY: Oxford University Press.
Hoeijmakers, J. H. J. (2001). Genome maintenance mechanisms for preventing cancer. Nature, 411, 366–374.
Richmond, T. H., & Davey, C. A. (2003). The structure of DNA in the nucleosome core. Nature, 423, 145–150.
Horn, P. J., & Peterson, C. L. (2002). Chromatin higher order folding: Wrapping up transcription. Science, 297, 1824–1827.
Quina, A. S., Buschbeck, M., & Di Croce, L. (2006). Chromatin structure and epigenetics. Biochemical Pharmacology, 72, 1563–1569.
Vargason, J. M., Eichman, B. F., & Ho, P. S. (2000). The extended and eccentric E-DNA structure induced by cytosine methylation or bromination. Nature Structural Biology, 7, 758–761.
Mayer-Jung, C., Moras, D., & Timsit, Y. (1998). Hydration and recognition of methylated CpG steps in DNA. EMBO Journal, 17, 2709–2718.
Schübeler, D., Lorincz, M. C., Cimbora, D. M., Telling, A., Feng, Y.-Q., Bouhassira, E. E., et al. (2000). Genomic targeting of methylated DNA: influence of methylation on transcription, replication, chromatin structure, and histone acetylation. Molecular and Cellular Biology, 20, 9103–9112.
Hashimshony, T., Zhang, J., Keshet, I., Bustin, M., & Ceder, H. (2003). The role of DNA methylation in setting up chromatin structure during development. Nature Genetics, 34, 187–192.
Okitsu, C. Y., & Hsieh, C. L. (2007). DNA methylation dictates histone H3K4 methylation. Molecular and Cellular Biology, 27, 2746–2757.
Irvine, R. A., Lin, I. G., & Hsieh, C.-L. (2002). DNA methylation has a local effect on transcription and histone acetylation. Molecular and Cellular Biology, 22, 6689–6696.
Bernstein, B. E., Meissner, A., & Lander, E. S. (2007). The mammalian epigenome. Cell, 128, 669–681.
Bernstein, B. E., Kamal, M., Lindblad-Toh, K., Bekiranov, S., Bailey, D. K., Huebert, D. J., et al. (2005). Genomic maps and comparative analysis of histone modifications in human and mouse. Cell, 120, 169–181.
Liang, G., Lin, J. C., Wei, V., Yoo, C., Cheng, J. C., Nguyen, C. T., et al. (2004). Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proceedings of the National Academy of Sciences of the USA, 101, 7357–7362.
Santos-Rosa, H., Schneider, R., Bannister, A. J., Sherriff, J., Bernstein, B. E., Emre, N. C., et al. (2002). Active genes are tri-methylated at K4 of histone H3. Nature, 419, 407–411.
Schneider, R. A., Bannister, J., Myers, F. A., Thorne, A. W., Crane-Robinson, C., et al. (2004). Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nature Cell Biology, 6, 73–77.
Christensen, J., Agger, K., Cloos, P. A., Pasini, D., Rose, S., Sennels, L., et al. (2007). RBP2 belongs to a family of demethylases, specific for tri- and dimethylated lysine 4 on histone 3. Cell, 128, 1063–1076.
Lorincz, M. C., Dickerson, D. R., Schmitt, M., & Groudine, M. (2004). Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nature Structural Molecular Biology, 11, 1068–1075.
Schübeler, D., MacAlpine, D. M., Scalzo, D., Wirbelauer, C., Kooperberg, C., van Leeuwen, F., et al. (2004). The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Development, 18, 1263–1271.
Parnell, T. J., & Geyer, P. K. (2000). Differences in insulator properties revealed by enhancer blocking assays on episomes. EMBO Journal, 19, 5864–5874.
Cook, P. R. (2003). Nongenic transcription, gene regulation and action at a distance. Cell Science, 116, 4483–4491.
Blanton, J., Gaszner, M., & Schedl, P. (2003). Protein–protein interactions and the pairing of boundary elements in vivo. Genes and Development, 17, 664–675.
Zhao, K., Hart, C. M., & Laemmli, U. K. (1995). Visualization of chromosomal domains with boundary element-associated factor BEAF-32. Cell, 81, 879–889.
Cai, H., & Levine, M. (1995). Modulation of enhancer–promoter interactions by insulators in the Drosophila embryo. Nature, 376, 533–536.
Ghosh, D., Gerasimova, T. I., & Corces, V. G. (2001). Interactions between the Su(Hw) and mod(mdg4) proteins required for gypsy insulator function. EMBO Journal, 20, 2518–2527.
Kellum, R., & Schedl, P. (1991). A position-effect assay for boundaries of higher order chromosomal domains. Cell, 64, 941–950.
Reither, S., Li, F., Gowher, H., & Jeltsch, A. (2003). Catalytic mechanism of DNA-(cytosine-C5)-methyltransferases revisited: Covalent intermediate formation is not essential for methyl group transfer by the murine Dnmt3a enzyme. Journal of Molecular Biology, 329, 675–684.
Christman, J. K. (2002). 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene, 21, 5483–5491.
Cedar, H., & Verdine, G. L. (1999). Gene expression: the amazing demethylase. Nature, 397, 568–569.
Cervoni, N., Detich, N., Seo, S. B., Chakravarti, D., & Szyf, M. (2002). The oncoprotein Set/TAF-1beta, an inhibitor of histone acetyltransferase, inhibits active demethylation of DNA, integrating DNA methylation and transcriptional silencing. Journal of Biological Chemistry, 277, 25026–25031.
Weiss, A., & Cedar, H. (1997). The role of DNA demethylation during development. Genes Cells, 2, 481–486.
Roberts, R. J., & Cheng, X. (1998). Base flipping. Annual Review of Biochemistry, 67, 181–198.
Kapoor, A., Agius, F., & Zhu, J.-K. (2005). Preventing transcriptional gene silencing by active DNA demethylation. FEBS Letters, 579, 5889–5898.
Jost, J. P., & Bruhat, A. (1997). The formation of DNA methylation patterns and the silencing of genes. Progress in Nucleic Acid Research and Molecular Biology, 57, 217–248.
Jost, J. P., Siegmann, M., Sun, L. J., & Leung, R. (1995). Mechanisms of DNA demethylation in chicken embryos: purification and properties of a 5-methylcytosine-DNA glycosylase. Journal of Biological Chemistry, 270, 9734–9739.
Weiss, A., Keshet, I., Razin, A., & Cedar, H. (1996). DNA demethylation in vitro: Involvement of RNA. Cell, 86, 709–718.
Swisher, J. F. A., Rand, E., Cedar, H., & Pyle, A. M. (1998). Analysis of putative RNase sensitivity and protease insensitivity of demethylation activity in extracts from rat myoblasts. Nucleic Acids Research, 26, 5573–5580.
Zhu, B., Zheng, Y., Angliker, H., Schwarz, S., Siegmann, M., Thiry, S., et al. (2000). 5-Methylcytosine DNA glycosylase activity is also present in the human MBD4 (G/T mismatch glycosylase) and in a related avian sequence. Nucleic Acids Research, 28, 4157–4165.
Zhu, B., Zheng, Y., Hess, D., Angliker, H., Schwarz, S., Siegmann, M., et al. (2000). 5-methylcytosine-DNA glycosylase activity is present in a cloned G/T mismatch DNA glycosylase associated with the chicken embryo DNA demethylation complex. Proceedings of the National Academy of Sciences of the USA, 97, 5135–5139.
Zhu, B., Benjamin, D., Zheng, Y., Angliker, H., Thiry, S., Siegmann, M., et al. (2001). Overexpression of 5-methylcytosine DNA glycosylase in human embryonic kidney cells EcR293 demethylates the promoter of a hormone-regulated reporter gene. Proceedings of the National Academy of Sciences of the USA, 98, 5031–5036.
Jost, J. P. (1993). Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyldeoxycytidine. Proceedings of the National Academy of Sciences of the USA, 90, 4684–4688.
Jost, J. P., Schwarz, S., Hess, D., Angliker, H., Fuller-Pace, F. V., Stahl, H. S., et al. (1999). A chicken embryo protein related to the mammalian DEAD box protein p68 is tightly associated with the highly purified protein–RNA complex of 5-MeC-DNA glycosylase. Nucleic Acids Research, 27, 3245–3252.
Vairapandi, M., & Duker, N. J. (1993). Enzymic removal of 5-methylcytosine from DNA by a human DNA-glycosylase. Nucleic Acids Research, 21, 5323–5327.
Vairapandi, M., Liebermann, D. A., Hoffman, B., & Duker, N. J. (2000). Human DNA-demethylating activity: A glycosylase associated with RNA and PCNA. Journal of Cellular Biochemistry, 79, 249–260.
Maga, G., & Hubscher, U. (2003). Proliferating cell nuclear antigen (PCNA): a dancer with many partners. Journal of Cell Science, 116, 3051–3060.
Hsieh, C. L. (1999). Evidence that protein binding specifies sites of DNA demethylation. Molecular and Cellular Biology, 19, 46–56.
Goelz, S. E., Vogelstein, B., Hamilton, S. R., & Feinberg, A. P. (1985). Hypomethylation of DNA from benign and malignant human colon neoplasms. Science, 228, 187–190.
Gaudet, F., Hodgson, J. G., Eden, A., Jakson-Grusby, L., Dausman, J., Gray, J. W., et al. (2003). Induction of tumors in mice by genomic hypomethylation. Science, 300, 489–492.
Gjerset, R. A., & Martin Jr., D. W. (1982). Presence of DNA demethylating activity in the nucleus of murine erythroleukemic cells. Journal of Biological Chemistry, 257, 8581–8583.
Ghoshal, K., Majumder, S., Datta, J., Motiwala, T., Bai, S., Sharma, S. M., et al. (2004). Role of human ribosomal RNA (rRNA) promoter methylation and of methyl-CpG-binding protein MBD2 in the suppression of rRNA gene expression. Journal of Biological Chemistry, 279, 6783–6793.
Zhu, Y., Brown, H. N., Zhang, Y., Holford, T. R., & Zheng, T. (2005). Genotypes and haplotypes of the methyl-CpG-binding domain 2 modify breast cancer risk dependent upon menopausal status. Breast Cancer Research, 7, R745–R752.
Fang, J. Y., Cheng, Z. H., Chen, Y. X., Lu, R., Yang, L., Zhu, H. Y., et al. (2004). Expression of Dnmt1, demethylase, MeCP2 and methylation of tumor-related genes in human gastric cancer. World Journal of Gastroenterologist, 10, 3394–3398.
Sansom, O. J., Berger, J., Bishop, S. M., Hendrich, B., Bird, A., & Clarke, A. R. (2003). Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nature Genetics, 34, 145–147 (also, see supplementary data).
Berger, J., Sansom, O., Clarke, A., & Bird, A. (2007). MBD2 is required for correct spatial gene expression in the gut. Molecular and Cellular Biology, 27, 4049–4057.
Galetzka, D., Weis, E., Tralau, T., Seidmann, L., & Haaf, T. (2007). Sex-specific windows for high mRNA expression of DNA methyltransferases 1 and 3A and methyl-CpG-binding domain proteins 2 and 4 in human fetal gonads. Molecular Reproduction and Development, 74, 233–241.
Mayer, W., Niveleau, A., Walter, J., Fundele, R., & Haaf, T. (2000). Demethylation of the zygotic paternal genome. Nature, 403, 501–502.
Dean, W., Santos, F., Stojkovic, M., Zakhartchenko, V., Walter, J., Wolf, E., et al. (2001). Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proceedings of the National Academy of Sciences of the USA, 98, 13734–13738.
Beaujean, N., Taylor, J. E., McGarry, M., Gardner, J. O., Wilmut, I., Loi, P., et al. (2004). The effect of interspecific oocytes on demethylation of sperm DNA. Proceedings of the National Academy of Sciences of the USA, 101, 7636–7640.
Kang, Y. K., Koo, D., Park, J. S., Choi, Y., Lee, K., & Han, Y. (2001). Influence of oocyte nuclei on demethylation of donor genome in cloned bovine embryos. FEBS Letters, 499, 55–58.
Wischnewski, F., Friese, O., Pantel, K., & Schwarzenbach, H. (2007). Methyl-CpG binding domain proteins and their involvement in the regulation of the MAGE-A1, MAGE-A2, MAGE-A3, and MAGE-A12 gene promoters. Molecular Cancer Research, 5, 749–759.
Bird, A. (2003). IL2 transcription unleashed by active DNA demethylation. Nature Immunology, 4, 208–209.
Erlanson, D., Dhen, L., & Verdin, G. L. (1993). Enzymatic DNA methylation through a locally unpaired intermediate. Journal of the American Chemical Society, 115, 12583–12584.
Chen, L., MacMillan, A. M., Cheng, W., Ezaz-Nikpay, K., Lane, W. S., & Verdin, G. L. (1991). Direct identification of the active site nucleophile in a DNA (cytosine-5-methyltransferase). Biochemistry, 30, 11018–11025.
Santi, D. V., Garrett, C. E., & Barr, P. J. (1983). On the mechanism of inhibition of DNA-cytosine methyltransferase by cytosine analogs. Cell, 33, 9–10.
Wilson, V. L., & Jones, P. A. (1983). Inhibition of DNA methylation by chemical carcinogens in vitro. Cell, 32, 239–246.
Klimasauskas, S., Kumar, S., Robert, R. J., & Cheng, X. (1994). HhaI methyltransferase flips its target base out of the DNA helix. Cell, 76, 357–369.
Wu, P., Qiu, C., Sohail, A., Zhang, X., Bhagwat, A. S., & Cheng, X. (2003). Mismatch repair in methylated DNA: Structure and activity of the mismatch-specific thymine glycosylase domain of methyl-CpG-binding protein MBD4. Journal of Biological Chemistry, 278, 5285–5291.
Miller, C. A., & Sweatt, J. D. (2007). Covalent modification of DNA regulates memory formation. Neuron, 53, 857–869.
Claus, R., Almstedt, M., & Lubbert, M. (2005). Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents. Seminars in Oncology, 32, 511–520.
Wijermans, P., Lubbert, M., Verhoef, G., Bosly, A., Ravoet, C., Andre, M., et al. (2000). Low-Dose 5-Aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: A multicenter phase II study in elderly patients. Journal of Clinical Oncology, 18, 956–965.
Yoo, C. B., & Jones, P. A. (2006). Epigenetic therapy of cancer: past, present and future. Nature Reviews Drug Discovery, 5, 37–50.
Mihich, E., & Jaenisch, R. (2004). Sixteenth annual pezcoller symposium: Stem cells and epigenesis in cancer. Cancer Research, 64, 8474–8477.
Sato, N., Maehara, N., Su, G. H., & Goggins, M. (2003). Effects of 5-aza-2′-deoxycytidine on matrix metalloproteinase expression and pancreatic cancer cell invasiveness. Journal of the National Cancer Institute, 95, 327–330.
Pulukuri, S. M., Estes, N., Patel, J., & Rao, J. S. (2007). Demethylation-linked activation of urokinase plasminogen activator is involved in progression of prostate cancer. Cancer Research, 67, 930–939.
Lucarelli, M., Fuso, A., Strom, R., & Scarpa, S. (2001). The dynamics of myogenin site-specific demethylation is strongly correlated with its expression and with muscle differentiation. Journal of Biological Chemistry, 276, 7500–7506.
El Kharroubi, A., Piras, G., & Stewart, C. L. (2001). DNA demethylation reactivates a subset of imprinted genes in uni-parental mouse embryonic fibroblasts. Journal of Biological Chemistry, 276, 8674–8680.
Santoso, B., Ortiz, B. D., & Winoto, A. (2000). Control of organ-specific demethylation by an element of the T-cell receptor-alpha locus control region. Journal of Biological Chemistry, 275, 1952–1858.
Ferguson, A. T., Vertino, P. M., Spitzner, J. R., Baylin, S. B., Muller, M. T., & Davidson, N. E. (1997). Role of estrogen receptor gene demethylation and DNA methyltransferase-DNA adduct formation in 5-aza-2′-deoxycytidine induced cytotoxicity in human breast cancer cells. Journal of Biological Chemistry, 272, 32260–32266.
Fuks, F., Burgers, W. A., Brehm, A., Hughes-Davies, L., & Kouzarides, T. (2000). DNA methyltransferase DNMT1 associates with histone deacetylase activity. Nature Genetics, 24, 88–91.
Wittschieben, B. O., Otero, G., de Bizemont, T., Fellows, J., Erdjument-Bromage, H., Ohba, R., et al. (1999). A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Molecular Cell, 4, 123–128.
Scaltriti, M., Belloni, L., Caporali, A., Davalli, P., Remondini, D., Rizzi, F., et al. (2006). Molecular classification of green tea catechin-sensitive and green tea catechin-resistant prostate cancer in the TRAMP mice model by quantitative real-time PCR gene profiling. Carcinogenesis, 27, 1047–1053.
Lund, P., Weisshaupt, K., Mikeska, T., Jammas, D., Chen, X., Kuban, R. J., et al. (2006). Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation. Oncogene, 25, 4890–4903.
Kundu, T. K., & Rao, M. R. S. (1999). CpG islands in chromatin organization and gene expression. Journal of Biochemistry, 125, 217–222.
Bock, C., Paulsen, M., Tierling, S., Mikeska, T., Lengauer, T., & Walter, J. (2006). CpG island methylation in human lymphocytes is highly correlated with DNA sequence, repeats, and predicted DNA structure. PLoS Genetics, 2, e26. doi:10.1371/journal.pgen.0020026.
Das, R., Dimitrova, N., Xuan, Z., Rollins, R. A., Haghighi, F., Edwards, J. R., et al. (2006). Computational prediction of methylation status in human genomic sequences. Proceedings of the National Academy of Sciences of the USA, 103, 10713–10716.
Rollins, R. A., Haghighi, F., Edwards, J. R., Das, R., Zhang, M. Q., Ju, J., et al. (2006). Large-scale structure of genomic methylation patterns. Genome Research, 16, 157–163.
Salisbury, C. M., & Cravatt, B. E. (2007). Activity based probes for profiling of histone deacetylase complexes. Proceedings of the National Academy of Sciences of the USA, 104, 1171–1176.
Delaval, K., Govin, J., Cerqueira, F., Rousseaux, S., Khochbin, S., & Feil, R. (2007). Differential histone modifications mark mouse imprinting control regions during spermatogenesis. EMBO Journal, 26, 720–729.
Frank, D., Keshet, I., Shani, M., Levine, A., Razin, A., & Ceder, H. (1991). Demethylation of CpG islands in embryonic cells. Nature, 351, 239–241.
Paroush, Z., Keshet, I., Yisraeli, J., & Ceder, H. (1990). Dynamics of demethylation and activation of the alpha-actin gene in myoblasts. Cell, 63, 1229–1237.
Wiechen, K., Diatchenko, L., Agoulink, A., Scharff, K. M., Schober, H., Arlt, K., et al. (2001). Caveolin-1 is down regulated in human ovarian carcinoma and Acts as candidate tumour suppressor gene. American Journal of Pathology, 159, 1635–1643.
Cui, J., Rohr, L. R., Swanson, G., Speights, V. O., Maxwell, T., & Brothman, A. R. (2001). Hypermethylation of the caveolin-1 gene promoter in prostate cancer. Prostate, 46, 249–256.
Liu, J., Ikeguchi, M., Nakamura, S., & Kaibara, N. (2002). Re-expression of the Cadherin–Catenin complex in lymph nodes with metastasis in advanced gastric cancer: the relationship with patient survival. Journal of Experimental and Clinical Cancer Research, 21, 65–71.
Foger, N., Marhaba, R., & Zoller, M. (2000). Involvement of CD44 in cytoskeleton rearrangement and raft reorganization in T cells. Journal of Cell Science, 114, 1169–1178.
Kito, H., Suzuki, H., Ichikawa, T., Sekita, N., Kamia, N., Akakura, K., et al. (2001). Hypermethylation of the CD44 gene is associated with progression and metastasis of human prostate cancer. Prostate, 49, 110–115.
Lou, W., Krill, D., Dhir, R., Becich, M. J., Dong, J.-T., Frierson Jr., H. F., et al. (1999). Methylation of CD44 metastasis suppressor gene in human prostate cancer. Cancer Research, 59, 2329–2331.
Hasegawa, M., Nelson, H. H., Peters, E., Ringstrom, E., Posner, M., & Kelsey, K. T. (2002). Patterns of gene promoter methylation in squamous cell cancer of the head and neck. Oncogene, 21, 4231–4236.
Hyman, R. (2002). Lack of a consistent relationship between demethylation of the CD44 promoter and CD44 expression. Immunogenetics, 53, 914–924.
Shiras, A., Bhosale, A., Patekar, A., Shepal, V., & Shastry, P. (2002). Differential expression of CD44(s) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines. Clinical & Experimental Metastasis, 19, 445–455.
Bankfalvi, A., KraBort, M., Buchwalow, I. B., Vegh, A., Felszeghy, E., & Piffko, J. (2002). Gains and loses of adhesion molecules (CD44, E-Cadherin, and b-Catenin) during oral carcinogenesis and tumour progression. Journal of Pathology, 198, 343–351.
Weber, G. F., Bronson, R. T., Ilagan, J., Cantor, H., Schmits, R., & Mak, T. W. (2002). Absence of the CD44 gene prevents sarcoma metastasis. Cancer Research, 62, 2281–2286.
Verkaik, N. S., Trapman, J., Romijn, J. C., Van Der Kwast, T. H., & Van Steenbrugge, G. J. (1999). Down regulation of CD44 expression in human prostatic carcinoma cell lines is correlated with DNA hypermethylation. International Journal of Cancer, 80, 439–443.
Kogerman, P., Sy, M.-S., & Culp, L. A. (1997). Counter-selection for over expressed human CD44s primary tumour versus lung metastases in mouse fibrosarcoma model. Oncogene, 15, 1407–1416.
Shiratori, H., Koshino, T., Uesugi, M., Nitto, H., & Saito, T. (2001). Acceleration of lung metastasis by up-regulation of CD44 expression in osteosarcoma-derived cell transplanted mice. Cancer Letters, 170, 177–182.
Ribeiro-Filho, L. A., Franks, J., Sasaki, M., Shiina, H., Li, L.-C., Nojima, D., et al. (2002). CpG hypermethylation of promoter region and Inactivation of E-cadherin gene in human bladder cancer. Molecular Carcinogenesis, 34, 187–198.
Karube, H., Masuda, H., Ishii, Y., & Takayama, T. (2002). E-Cadherin expression is inversely proportional to tumour size in experimental liver metastasis. Journal of Surgical Research, 106, 173–178.
Alpaugh, M. L., Tomlinson, J. S., Kasraeian, S., & Barsky, S. H. (2002). Cooperative role of E-Cadherin sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumour emboli in inflammatory breast carcinoma. Oncogene, 21, 3631–3643.
Ikeguchi, M., Makino, M., & Kaibara, N. (2001). Clinical significance of E-Cadherin–Cateninn complex expression in metastatic foci of colorectal carcinoma. Journal of Surgical Research, 77, 201–207.
Kase, S., Sugio, K., Yamazaki, K., Okamoto, T., Yano, T., & Sugimachi, K. (2000). Expression of E-Cadherin and b-Catenin in human non-small cell lung cancer and the clinical significance. Clinical Cancer Research, 6, 4784–4796.
Kleer, C. G., van Golen, K. L., Braun, T., & Merajver, S. D. (2001). Persistant E-Cadherin expression in inflammatory breast cancer. Modern Pathology, 14, 458–464.
Jiang, W. G., & Mansel, R. E. (2000). E-cadherin complex and its abnormalities in human breast cancer. Surgical Oncology, 9, 151–171.
Cavalli, L. R., Urban, C. A., Dai, D., de Assis, S., Tavares, D. C., Rone, J. D., et al. (2003). Genetic and epigenetic alterations in sentinel lymph nodes metastatic lesions compared to their corresponding primary breast tumors. Cancer Genetics and Cytogenetics, 146, 33–40.
Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420, 860–867.
Dong, E., Guidotti, A., Grayson, D. R., & Costa, E. (2007). Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters. Proceedings of the National Academy of Sciences of the USA, 104, 4676–4681.
Wong, I. H. (2001). Methylation profiling of human cancers in blood: molecular monitoring and prognostication (Review). International Journal of Oncology, 19, 1319–1324.
Baylin, S. B., & Ohm, J. E. (2006). Epigenetic gene silencing in cancer—A mechanism for early oncogenic pathway addiction. Nature Reviews, Cancer, 6, 107–116.
Jones, P. A., & Baylin, S. B. (2007). The epigenomics of cancer. Cell, 128, 683–692.
Zhu, X., Leav, I., Leung, Y. K., Wu, M., Liu, Q., Gao, Y., et al. (2004). Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis. American Journal of Pathology, 164, 2003–2012.
Zhu, J., & Yao, X. (2007). Use of DNA methylation for cancer detection and molecular classification. Journal of Biochemistry and Molecular Biology, 40, 135–141.
Li, L. C., Okino, S. T., & Dahiya, R. (2004). DNA methylation in prostate cancer (Review). Biochimica et Biophysica Acta, 1704, 87–102.
Fang, M. Z., Wang, Y., Ai, N., Hou, Z., Sun, Y., Lu, H., et al. (2003). Tea polyphenol Epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer Cell lines. Cancer Research, 63, 7563–7570.
Pakneshan, P., Szyf, M., Farias-Eisner, R., & Rabbani, S. A. (2004). Reversal of the hypomethylation status of urokinase (uPA) promoter blocks breast cancer growth and metastasis. Journal of Biological Chemistry, 279, 31735–31744.
Peterson, C. L., & Logie, C. (2000). Recruitment of chromatin remodeling machines. Journal of Cellular Biochemistry, 78, 179–185.
Rhee, I., Jair, K.-W., Yen, R.-W. C., Lengauer, C., Herman, J. G., Kinzler, K. W., et al. (2000). CpG methylation is maintained in human cancer cells lacking DNMT1. Nature, 404, 1003–1007.
Razin, A., Cedar, H., & Riggs, A. D. (1984). DNA methylation, biochemistry, and biological significance. New York: Springer.
Adams, R. L. P., & Burdon, R. H. (1985). Molecular biology of DNA methylation. New York: Springer.
Jost, J.-P., & Saluz, H. P. (1993). DNA methylation: Molecular biology and biological significance. Berlin: Birkhäuser.
Shell, S., Park, S. M., Radjabi, A. R., Schickel, R., Kistner, E. O., Jewell, D. A., et al. (2007). Let-7 expression defines two differentiation stages of cancer. Proceedings of the National Academy of Sciences of the USA, 104, 11400–11405.
Acknowledgements
The work was done in part at the McGill University, Montreal, Canada, during one of the authors (SKP) stay as academic trainee staff, supported by a fellowship from the National Cancer Institute of Canada (NCIC); and also done in part at the University of California at San Francisco, USA, during the stay of SKP and AP as postdoctoral scientists supported by fellowships from NIH, and thereafter from NCIRE, California, USA. Grant support for SB: ABO Project 2006, Venezia, Italy; AICR (UK) Grant No. 06-711; Istituto Nazionale Biostrutture e Biosistemi (INBB), Roma; Associazione Assistenza Tumori Alto Adige—Südtiroler Krebshilfe, Bolzano (Bozen), Italy. We apologize to those, whose work and related publications we have not been able to discuss and cite due to space limitations.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Patra, S.K., Patra, A., Rizzi, F. et al. Demethylation of (Cytosine-5-C-methyl) DNA and regulation of transcription in the epigenetic pathways of cancer development. Cancer Metastasis Rev 27, 315–334 (2008). https://doi.org/10.1007/s10555-008-9118-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10555-008-9118-y