Role of Epigenetics in Cancer Initiation and Progression

  • Flora Chik
  • Moshe Szyf
  • Shafaat A. Rabbani
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 720)


The epigenome which comprises DNA methylation, histone modifications, chromatin structures and non-coding RNAs controls gene expression patterns. In cancer cells, there are aberrant changes in the epigenome. The question in cancer epigenetics is that whether these changes are the cause of cell transformation, or rather the consequence of it. We will discuss the epigenetic phenomenon in cancer, as well as the recent interests in the epigenetic reprogramming events, and their implications in the cancer stem cell theory. We will also look at the progression of cancers as they become more aggressive, with focus on the role of epigenetics in tumor metastases exemplified with the urokinase plasminogen activator (uPA) system. Last but not least, with therapeutics intervention in mind, we will highlight the importance of balance in the design of epigenetic based anti-cancer therapeutic strategies.


Proliferate Cell Nuclear Antigen Normal Stem Cell Epigenetic Reprogram DNMT1 Inhibitor Global Hypomethylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Board E (2008) Moving ahead with an international human epigenome project. Nature 454:711–715CrossRefGoogle Scholar
  2. 2.
    Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089–1093PubMedCrossRefGoogle Scholar
  3. 3.
    McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B et al (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348PubMedCrossRefGoogle Scholar
  4. 4.
    Wolff GL, Kodell RL, Moore SR, Cooney CA (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12:949–957PubMedGoogle Scholar
  5. 5.
    Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254PubMedCrossRefGoogle Scholar
  6. 6.
    Brown SE, Szyf M (2008) Dynamic epigenetic states of ribosomal RNA promoters during the cell cycle. Cell Cycle 7:382–390PubMedCrossRefGoogle Scholar
  7. 7.
    Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M et al (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295:1079–1082PubMedCrossRefGoogle Scholar
  8. 8.
    Razin A, Riggs AD (1980) DNA methylation and gene function. Science 210:604–610PubMedCrossRefGoogle Scholar
  9. 9.
    Kim G-D, Ni J, Kelesoglu N, Roberts RJ, Pradhan S (2002) Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. EMBO J 21:4183–4195PubMedCrossRefGoogle Scholar
  10. 10.
    Szyf M, Schimmer BP, Seidman JG (1989) Nucleotide-sequence-specific de novo methylation in a somatic murine cell line. Proc Natl Acad Sci USA 86:6853–6857PubMedCrossRefGoogle Scholar
  11. 11.
    Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298PubMedCrossRefGoogle Scholar
  12. 12.
    Pirola L, Balcerczyk A, Okabe J, El-Osta A (2010) Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol 6(12):665–75PubMedCrossRefGoogle Scholar
  13. 13.
    Ling C, Groop L (2009) Epigenetics: a molecular link between environmental factors and type 2 ­diabetes. Diabetes 58:2718–2725PubMedCrossRefGoogle Scholar
  14. 14.
    Sharma P, Kumar J, Garg G, Kumar A, Patowary A et al (2008) Detection of altered global DNA methylation in coronary artery disease patients. DNA Cell Biol 27:357–365PubMedCrossRefGoogle Scholar
  15. 15.
    Abel T, Zukin RS (2008) Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol 8:57–64PubMedCrossRefGoogle Scholar
  16. 16.
    Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92PubMedCrossRefGoogle Scholar
  17. 17.
    Ruo-Kai L, Han-Shui H, Jer-Wei C, Chih-Yi C, Jung-Ta C et al (2007) Alteration of DNA methyltransferases contributes to 5′CpG methylation and poor prognosis in lung cancer. Lung Cancer 55:205–213CrossRefGoogle Scholar
  18. 18.
    Saito Y, Kanai Y, Nakagawa T, Sakamoto M, Saito H et al (2003) Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int J Cancer 105:527–532PubMedCrossRefGoogle Scholar
  19. 19.
    Girault I, Tozlu S, Lidereau R, Bièche I (2003) Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin Cancer Res 9:4415–4422PubMedGoogle Scholar
  20. 20.
    Etoh T, Kanai Y, Ushijima S, Nakagawa T, Nakanishi Y et al (2004) Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol 164:689–699PubMedCrossRefGoogle Scholar
  21. 21.
    S-I M, Chijiwa T, Okamura T, Akashi K, Fukumaki Y et al (2001) Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 97:1172–1179CrossRefGoogle Scholar
  22. 22.
    Qu Y, Mu G, Wu Y, Dai X, Zhou F et al (2010) Overexpression of DNA methyltransferases 1, 3a, and 3b significantly correlates with retinoblastoma tumorigenesis. Am J Clin Pathol 134:826–834PubMedCrossRefGoogle Scholar
  23. 23.
    Rhee I, Bachman KE, Park BH, Jair KW, Yen RW et al (2002) DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416:552–556PubMedCrossRefGoogle Scholar
  24. 24.
    Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC et al (2003) DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet 33:61–65PubMedCrossRefGoogle Scholar
  25. 25.
    Sato H, Oka T, Shinnou Y, Kondo T, Washio K et al (2010) Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma. Am J Pathol 176:402–415PubMedCrossRefGoogle Scholar
  26. 26.
    Niklinska W, Naumnik W, Sulewska A, Kozłowski M, Pankiewicz W et al (2009) Prognostic significance of DAPK and RASSF1A promoter hypermethylation in non-small cell lung cancer (NSCLC). Folia Histochem Cytobiol 47:275–280PubMedCrossRefGoogle Scholar
  27. 27.
    Braggio E, Maiolino A, Gouveia M, Magalhães R, Souto Filho J et al (2010) Methylation status of nine tumor suppressor genes in multiple myeloma. Int J Hematol 91:87–96PubMedCrossRefGoogle Scholar
  28. 28.
    Pakneshan P, Têtu B, Rabbani SA (2004) Demethylation of urokinase promoter as a prognostic marker in patients with breast carcinoma. Clin Cancer Res 10:3035–3041PubMedCrossRefGoogle Scholar
  29. 29.
    Sharma G, Mirza S, Parshad R, Srivastava A, Datta Gupta S et al (2010) CpG hypomethylation of MDR1 gene in tumor and serum of invasive ductal breast carcinoma patients. Clin Biochem 43:373–379PubMedCrossRefGoogle Scholar
  30. 30.
    Muller CI, Ruter B, Koeffler HP, Lubbert M (2006) DNA hypermethylation of myeloid cells, a novel therapeutic target in MDS and AML. Curr Pharm Biotechnol 7:315–321PubMedCrossRefGoogle Scholar
  31. 31.
    Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M et al (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106:1794–1803PubMedCrossRefGoogle Scholar
  32. 32.
    Anon (2003) Decitabine: 2’-deoxy-5-azacytidine, Aza dC, DAC, dezocitidine, NSC 127716. Drugs R D 4:352–358Google Scholar
  33. 33.
    Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28PubMedCrossRefGoogle Scholar
  34. 34.
    Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079PubMedGoogle Scholar
  35. 35.
    Lengauer C, Kinzler KW, Vogelstein B (1997) DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci USA 94:2545–2550PubMedCrossRefGoogle Scholar
  36. 36.
    McKenna ES, Sansam CG, Cho YJ, Greulich H, Evans JA et al (2008) Loss of the epigenetic tumor suppressor snf5 leads to cancer without genomic instability. Mol Cell Biol 28:6223–6233PubMedCrossRefGoogle Scholar
  37. 37.
    Kohashi K, Oda Y, Yamamoto H, Tamiya S, Oshiro Y et al (2008) SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma. Am J Surg Pathol 32:1168–1174PubMedCrossRefGoogle Scholar
  38. 38.
    Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, Gore L, Feusner JH (2009) Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer 52:328–334PubMedCrossRefGoogle Scholar
  39. 39.
    Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM et al (1999) Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74–79PubMedGoogle Scholar
  40. 40.
    Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M (1988) Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 48:1159–1161PubMedGoogle Scholar
  41. 41.
    Finch PW, He X, Kelley MJ, Uren A, Schaudies RP et al (1997) Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Proc Natl Acad Sci USA 94:6770–6775PubMedCrossRefGoogle Scholar
  42. 42.
    Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD et al (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417–422PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang W, Glockner SC, Guo M, Machida EO, Wang DH et al (2008) Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res 68:2764–2772PubMedCrossRefGoogle Scholar
  44. 44.
    Yan PS, Venkataramu C, Ibrahim A, Liu JC, Shen RZ et al (2006) Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue. Clin Cancer Res 12:6626–6636PubMedCrossRefGoogle Scholar
  45. 45.
    Cheng AS, Culhane AC, Chan MW, Venkataramu CR, Ehrich M et al (2008) Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer Res 68:1786–1796PubMedCrossRefGoogle Scholar
  46. 46.
    Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395:89–93PubMedCrossRefGoogle Scholar
  47. 47.
    MacLeod AR, Szyf M (1995) Expression of antisense to DNA methyltransferase mRNA induces DNA demethylation and inhibits tumorigenesis. J Biol Chem 270:8037–8043PubMedCrossRefGoogle Scholar
  48. 48.
    Ramchandani S, MacLeod AR, Pinard M, von Hofe E, Szyf M (1997) Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide. Proc Natl Acad Sci USA 94:684–689PubMedCrossRefGoogle Scholar
  49. 49.
    Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H (2005) Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci USA 102:8905–8909PubMedCrossRefGoogle Scholar
  50. 50.
    Ha K, Lee GE, Palii SS, Brown KD, Takeda Y et al (2011) Rapid and transient recruitment of DNMT1 to DNA double-strand breaks is mediated by its interaction with multiple components of the DNA damage response machinery. Hum Mol Genet 20(1):126–40PubMedCrossRefGoogle Scholar
  51. 51.
    Milutinovic S, Zhuang Q, Niveleau A, Szyf M (2003) Epigenomic stress response. Knockdown of DNA methyltransferase 1 triggers an intra-S-phase arrest of DNA replication and induction of stress response genes. J Biol Chem 278:14985–14995PubMedCrossRefGoogle Scholar
  52. 52.
    Unterberger A, Andrews SD, Weaver IC, Szyf M (2006) DNA methyltransferase 1 knockdown activates a replication stress checkpoint. Mol Cell Biol 26:7575–7586PubMedCrossRefGoogle Scholar
  53. 53.
    Chen T, Hevi S, Gay F, Tsujimoto N, He T et al (2007) Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Nat Genet 39:391–396PubMedCrossRefGoogle Scholar
  54. 54.
    Palii SS, Van Emburgh BO, Sankpal UT, Brown KD, Robertson KD (2008) DNA methylation inhibitor 5-Aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol 28:752–771PubMedCrossRefGoogle Scholar
  55. 55.
    Rountree MR, Bachman KE, Baylin SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25:269–277PubMedCrossRefGoogle Scholar
  56. 56.
    Negishi M, Chiba T, Saraya A, Miyagi S, Iwama A (2009) Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process. Genes Cells 14:1347–1357PubMedCrossRefGoogle Scholar
  57. 57.
    Koizumi T, Negishi M, Nakamura S, Oguro H, Satoh K et al (2010) Depletion of Dnmt1-associated protein 1 triggers DNA damage and compromises the proliferative capacity of hematopoietic stem cells. Int J Hematol 91:611–619PubMedCrossRefGoogle Scholar
  58. 58.
    Hochberg Z, Feil R, Constancia M, Fraga M, Junien C et al (2010) Child health, developmental plasticity, and epigenetic programming. Endocr Rev 32(2):159–224PubMedCrossRefGoogle Scholar
  59. 59.
    Chiu CP, Blau HM (1984) Reprogramming cell differentiation in the absence of DNA synthesis. Cell 37:879–887PubMedCrossRefGoogle Scholar
  60. 60.
    Chiu CP, Blau HM (1985) 5-Azacytidine permits gene activation in a previously noninducible cell type. Cell 40:417–424PubMedCrossRefGoogle Scholar
  61. 61.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  62. 62.
    McGinnis W, Garber RL, Wirz J, Kuroiwa A, Gehring WJ (1984) A homologous protein-coding sequence in drosophila homeotic genes and its conservation in other metazoans. Cell 37:403–408PubMedCrossRefGoogle Scholar
  63. 63.
    Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K (2006) Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 20:1123–1136PubMedCrossRefGoogle Scholar
  64. 64.
    Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326PubMedCrossRefGoogle Scholar
  65. 65.
    Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE et al (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237–242PubMedCrossRefGoogle Scholar
  66. 66.
    Vire E, Brenner C, Deplus R, Blanchon L, Fraga M et al (2006) The polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874PubMedCrossRefGoogle Scholar
  67. 67.
    Jordan CT (2009) Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 4:203–205PubMedCrossRefGoogle Scholar
  68. 68.
    Hong D, Gupta R, Ancliff P, Atzberger A, Brown J et al (2008) Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 319:336–339PubMedCrossRefGoogle Scholar
  69. 69.
    Mullighan CG, Phillips LA, Su X, Ma J, Miller CB et al (2008) Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322:1377–1380PubMedCrossRefGoogle Scholar
  70. 70.
    Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39:157–158PubMedCrossRefGoogle Scholar
  71. 71.
    Passegue E, Jamieson CH, Ailles LE, Weissman IL (2003) Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci USA 100(Suppl 1):11842–11849PubMedCrossRefGoogle Scholar
  72. 72.
    Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902PubMedCrossRefGoogle Scholar
  73. 73.
    Jordan CT, Guzman ML, Noble M (2006) Cancer stem cells. N Engl J Med 355:1253–1261PubMedCrossRefGoogle Scholar
  74. 74.
    Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y et al (2006) Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9. Nature 442:818–822PubMedCrossRefGoogle Scholar
  75. 75.
    Pulukuri SMK, Gorantla B, Dasari VR, Gondi CS, Rao JS (2010) Epigenetic upregulation of urokinase plasminogen activator promotes the tropism of mesenchymal stem cells for tumor cells. Mol Cancer Res 8:1074–1083PubMedCrossRefGoogle Scholar
  76. 76.
    Zhao D, Najbauer J, Garcia E, Metz MZ, Gutova M et al (2008) Neural stem cell tropism to glioma: critical role of tumor hypoxia. Mol Cancer Res 6:1819–1829PubMedCrossRefGoogle Scholar
  77. 77.
    Thompson EW, Newgreen DF, Tarin D (2005) Carcinoma invasion and metastasis: a role for ­epithelial-mesenchymal transition? Cancer Res 65:5991–5995, discussion 5995PubMedCrossRefGoogle Scholar
  78. 78.
    Risbridger GP, Davis ID, Birrell SN, Tilley WD (2010) Breast and prostate cancer: more similar than different. Nat Rev Cancer 10:205–212PubMedCrossRefGoogle Scholar
  79. 79.
    Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695PubMedCrossRefGoogle Scholar
  80. 80.
    Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRefGoogle Scholar
  81. 81.
    Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G et al (2008) Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68:989–997PubMedCrossRefGoogle Scholar
  82. 82.
    Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R et al (1995) E-cadherin expression is silenced by dna hypermethylation in human breast and prostate carcinomas. Cancer Res 55:5195–5199PubMedGoogle Scholar
  83. 83.
    von Burstin J, Eser S, Paul MC, Seidler B, Brandl M et al (2009) E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology 137:361–371CrossRefGoogle Scholar
  84. 84.
    Lei W, Zhang K, Pan X, Hu Y, Wang D et al (2010) Histone deacetylase 1 is required for transforming growth factor-[beta]1-induced epithelial-mesenchymal transition. Int J Biochem Cell Biol 42:1489–1497PubMedCrossRefGoogle Scholar
  85. 85.
    Su H-Y, Lai H-C, Lin Y-W, Liu C-Y, Chen C-K et al (2010) Epigenetic silencing of SFRP5 is related to malignant phenotype and chemoresistance of ovarian cancer through Wnt signaling pathway. Int J Cancer 127:555–567PubMedCrossRefGoogle Scholar
  86. 86.
    Kawakami K, Yamamura S, Hirata H, Ueno K, Saini S et al (2010) Secreted frizzled-related protein-5 (sFRP-5) is epigenetically downregulated and functions as a tumor suppressor in kidney cancer. Int J Cancer 128(3):541–50CrossRefGoogle Scholar
  87. 87.
    Xue C, Plieth D, Venkov C, Xu C, Neilson EG (2003) The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res 63:3386–3394PubMedGoogle Scholar
  88. 88.
    Nagaraja GM, Othman M, Fox BP, Alsaber R, Pellegrino CM et al (2006) Gene expression signatures and biomarkers of noninvasive and invasive breast cancer cells: comprehensive profiles by representational difference analysis, microarrays and proteomics. Oncogene 25:2328–2338PubMedCrossRefGoogle Scholar
  89. 89.
    Ma X, Yang Y, Wang Y, An G, Lv G (2010) Small interfering RNA-directed knockdown of S100A4 decreases proliferation and invasiveness of osteosarcoma cells. Cancer Lett 299:171–181PubMedCrossRefGoogle Scholar
  90. 90.
    Parfyonova YV, Plekhanova OS, Tkachuk VA (2002) Plasminogen activators in vascular remodeling and angiogenesis. Biochemistry (Mosc) 67:119–134CrossRefGoogle Scholar
  91. 91.
    Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM et al (1980) Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284:67–68PubMedCrossRefGoogle Scholar
  92. 92.
    Mazar A, Henkin J, Goldfarb R (1999) The urokinase plasminogen activator system in cancer: implications for tumor angiogenesis and metastasis. Angiogenesis 3:15–32PubMedCrossRefGoogle Scholar
  93. 93.
    Møller LB, Pöllänen J, Rønne E, Pedersen N, Blasi F (1993) N-linked glycosylation of the ligand-binding domain of the human urokinase receptor contributes to the affinity for its ligand. J Biol Chem 268:11152–11159PubMedGoogle Scholar
  94. 94.
    Estreicher A, Muhlhauser J, Carpentier JL, Orci L, Vassalli JD (1990) The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 111:783–792PubMedCrossRefGoogle Scholar
  95. 95.
    Limongi P, Resnati M, Hernandez-Marrero L, Cremona O, Blasi F et al (1995) Biosynthesis and apical localization of the urokinase receptor in polarized MDCK epithelial cells. FEBS Lett 369:207–211PubMedCrossRefGoogle Scholar
  96. 96.
    Quax PH, van Leeuwen RT, Verspaget HW, Verheijen JH (1990) Protein and messenger RNA levels of plasminogen activators and inhibitors analyzed in 22 human tumor cell lines. Cancer Res 50:1488–1494PubMedGoogle Scholar
  97. 97.
    Rabbani SA, Mazar AP (2001) The role of the plasminogen activation system in angiogenesis and metastasis. Surg Oncol Clin N Am 10:393–415, xGoogle Scholar
  98. 98.
    Rabbani SA, Xing RH (1998) Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies. Int J Oncol 12:911–920PubMedGoogle Scholar
  99. 99.
    Guo Y, Pakneshan P, Gladu J, Slack A, Szyf M et al (2002) Regulation of DNA methylation in human breast cancer. Effect on the urokinase-type plasminogen activator gene production and tumor invasion. J Biol Chem 277:41571–41579PubMedCrossRefGoogle Scholar
  100. 100.
    Pakneshan P, Szyf M, Farias-Eisner R, Rabbani SA (2004) Reversal of the hypomethylation status of urokinase (uPA) promoter blocks breast cancer growth and metastasis. J Biol Chem 279:31735–31744PubMedCrossRefGoogle Scholar
  101. 101.
    Shukeir N, Pakneshan P, Chen G, Szyf M, Rabbani SA (2006) Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo. Cancer Res 66:9202–9210PubMedCrossRefGoogle Scholar
  102. 102.
    Zhao Y, Li JS, Guo MZ, Feng BS, Zhang JP (2010) Inhibitory effect of S-adenosylmethionine on the growth of human gastric cancer cells in vivo and in vitro. Chin J Cancer 29:752–760PubMedCrossRefGoogle Scholar
  103. 103.
    Detich N, Hamm S, Just G, Knox JD, Szyf M (2003) The methyl donor s-adenosylmethionine inhibits active demethylation of dna: a candidate novel mechanism for the pharmacological effects of S-adenosylmethionine. J Biol Chem 278:20812–20820PubMedCrossRefGoogle Scholar
  104. 104.
    Xing J, Stewart DJ, Gu J, Lu C, Spitz MR et al (2008) Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer. Br J Cancer 98:1716–1722PubMedCrossRefGoogle Scholar
  105. 105.
    Campbell PM, Bovenzi V, Szyf M (2004) Methylated DNA-binding protein 2 antisense inhibitors suppress tumourigenesis of human cancer cell lines in vitro and in vivo. Carcinogenesis 25:499–507PubMedCrossRefGoogle Scholar
  106. 106.
    Ivanov MA, Lamrihi B, Szyf M, Scherman D, Bigey P (2003) Enhanced antitumor activity of a combination of MBD2-antisense electrotransfer gene therapy and bleomycin electrochemotherapy. J Gene Med 5:893–899PubMedCrossRefGoogle Scholar
  107. 107.
    Champion C, Guianvarc’h D, Senamaud-Beaufort C, Jurkowska RZ, Jeltsch A et al (2010) Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine. PLoS One 5:e12388PubMedCrossRefGoogle Scholar
  108. 108.
    Ateeq B, Unterberger A, Szyf M, Rabbani SA (2008) Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo. Neoplasia 10:266–278PubMedGoogle Scholar
  109. 109.
    Chik F, Szyf M (2010) Effects of specific DNMT-gene depletion on cancer cell transformation and breast cancer cell invasion; towards selective DNMT inhibitors. Carcinogenesis 32(2):224–32PubMedCrossRefGoogle Scholar
  110. 110.
    Frost P, Kerbel RS, Hunt B, Man S, Pathak S (1987) Selection of metastatic variants with identifiable karyotypic changes from a nonmetastatic murine tumor after treatment with 2′-deoxy-5-azacytidine or hydroxyurea: implications for the mechanisms of tumor progression. Cancer Res 47:2690–2695PubMedGoogle Scholar
  111. 111.
    Yu Y, Zeng P, Xiong J, Liu Z, Berger SL et al (2010) Epigenetic drugs can stimulate metastasis through enhanced expression of the pro-metastatic ezrin gene. PLoS One 5:e12710PubMedCrossRefGoogle Scholar
  112. 112.
    Jung Y, Park J, Kim TY, Park JH, Jong HS et al (2007) Potential advantages of DNA methyltransferase 1 (DNMT1)-targeted inhibition for cancer therapy. J Mol Med 85:1137–1148PubMedCrossRefGoogle Scholar
  113. 113.
    Szyf M, Pakneshan P, Rabbani SA (2004) DNA demethylation and cancer: therapeutic implications. Cancer Lett 211:133–143PubMedCrossRefGoogle Scholar
  114. 114.
    Szyf M, Pakneshan P, Rabbani SA (2004) DNA methylation and breast cancer. Biochem Pharmacol 68:1187–1197PubMedCrossRefGoogle Scholar
  115. 115.
    Szyf M (2009) Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol 49:243–263PubMedCrossRefGoogle Scholar
  116. 116.
    Szyf M (2005) DNA methylation and demethylation as targets for anticancer therapy. Biochemistry (Mosc) 70:533–549CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pharmacology and TherapeuticsMcGill UniversityMontrealCanada
  2. 2.Sackler Program for Epigenetics and Developmental PsychobiologyMcGill UniversityMontrealCanada
  3. 3.Department of MedicineMcGill University Health CentreMontrealCanada

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