Skip to main content
SpringerLink
Log in
Book cover

Pancreatic Cancer pp 177–208Cite as

Epigenetics and Its Applications to the Progression Model of Pancreatic Cancer

  • Reference work entry
  • First Online:

  • 1980 Accesses

Abstract

Defined as heritable changes in gene expression, which are not due to any alteration in the DNA sequence, epigenetic pathways have come to the forefront of research in disease, and in particular, cancer. In fact, these pathways are more prevalently altered in cancer than genetic alterations and most important, can be reversible, lending themselves as attractive therapeutic targets. This chapter will cover the basic aspects of transcriptional gene regulation, epigenetics, and chromatin dynamics and then focus on the intricacies of its application to pancreatic cancer biology and potential therapeutics. In addition, a model for better understanding pancreatic cancer is outlined to expand the highly provocative and productive “mutation centric” progression model, as defined by Hruban and colleagues, into a current model that formally includes chromatin-induced and noncoding RNA-induced epigenetic changes, as well as other alterations that result from changes in nuclear shape. This model offers a compass for further considerations aimed at illuminating the field of pancreatic cancer biology, diagnosis, therapeutics, and chemoprevention, in a similar, prolific manner as the original model.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   849.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   1,099.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6:2969–72.

    CAS  PubMed  Google Scholar 

  2. Kuhn TS. The structure of scientific revolutions. 1st ed. Chicago: University of Chicago Press; 1996.

    Book  Google Scholar 

  3. Jacob F, Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol. 1961;3:318–56.

    Article  CAS  PubMed  Google Scholar 

  4. McClure WR. Mechanism and control of transcription initiation in prokaryotes. Annu Rev Biochem. 1985;54:171–204.

    Article  CAS  PubMed  Google Scholar 

  5. Ebright RH. RNA polymerase: structural similarities between bacterial RNA polymerase and eukaryotic RNA polymerase II. J Mol Biol. 2000;304:687–98.

    Article  CAS  PubMed  Google Scholar 

  6. Roeder RG, Rutter WJ. Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms. Nature. 1969;224:234–7.

    Article  CAS  PubMed  Google Scholar 

  7. Chambon P. Eukaryotic nuclear RNA polymerases. Annu Rev Biochem. 1975;44:613–38.

    Article  CAS  PubMed  Google Scholar 

  8. Roeder RG. Eukaryotic nuclear RNA polymerases. In: Losick R, Chamberlin M, editors. RNA polymerase. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 1976. p. 285–329.

    Google Scholar 

  9. Koleske AJ, Young RA. The RNA polymerase II holoenzyme and its implications for gene regulation. Trends Biochem Sci. 1995;20:113–6.

    Article  CAS  PubMed  Google Scholar 

  10. Orphanides G, Lagrange T, Reinberg D. The general transcription factors of RNA polymerase II. Genes Dev. 1996;10:2657–83.

    Article  CAS  PubMed  Google Scholar 

  11. Li Y, Flanagan PM, Tschochner H, Kornberg RD. RNA polymerase II initiation factor interactions and transcription start site selection. Science. 1994;263:805–7.

    Article  CAS  PubMed  Google Scholar 

  12. Myers LC, Kornberg RD. Mediator of transcriptional regulation. Annu Rev Biochem. 2000;69:729–49.

    Article  CAS  PubMed  Google Scholar 

  13. Istrail S, Davidson EH. Logic functions of the genomic cis-regulatory code. Proc Natl Acad Sci U S A. 2005;102:4954–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cook T, Gebelein B, Mesa K, Mladek A, Urrutia R. Molecular cloning and characterization of TIEG2 reveals a new subfamily of transforming growth factor-beta -inducible Sp1-like zinc finger-encoding genes involved in the regulation of cell growth. J Biol Chem. 1998;273:25929–36.

    Article  CAS  PubMed  Google Scholar 

  15. Rose SD, Swift GH, Peyton MJ, Hammer RE, MacDonald RJ. The role of PTF1-P48 in pancreatic acinar gene expression. J Biol Chem. 2001;276:44018–26.

    Article  CAS  PubMed  Google Scholar 

  16. Jan J. Gene regulatory factors in pancreatic development. Dev Dyn. 2004;229:176–200.

    Article  CAS  Google Scholar 

  17. Jones N. Structure and function of transcription factors. Semin Cancer Biol. 1990;1:5–17.

    CAS  PubMed  Google Scholar 

  18. Mitchell PJ, Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989;245:371–8.

    Article  CAS  PubMed  Google Scholar 

  19. Kadonaga JT. Regulation of RNA polymerase II transcription by sequence-specific DNA binding factors. Cell. 2004;116:247–57.

    Article  CAS  PubMed  Google Scholar 

  20. Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene. 2007;26:5420–32.

    Article  CAS  PubMed  Google Scholar 

  21. Manal M, Chandrasekar MJN, Gomathi Priya J, Nanjan MJ. Inhibitors of histone deacetylase as antitumor agents: a critical review. Bioorg Chem. 2016;67:18–42.

    Article  CAS  PubMed  Google Scholar 

  22. Pazin MJ, Kadonaga JT. What's up and down with histone deacetylation and transcription? Cell. 1997;89:325–8.

    Article  CAS  PubMed  Google Scholar 

  23. Sterner DE, Berger SL. Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev. 2000;64:435–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kornberg RD. Chromatin structure: a repeating unit of histones and DNA. Science. 1974;184:868–71.

    Article  CAS  PubMed  Google Scholar 

  25. Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell. 1999;98:285–94.

    Article  CAS  PubMed  Google Scholar 

  26. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403:41–5.

    Article  CAS  PubMed  Google Scholar 

  27. Rizzo PJ. Basic chromosomal proteins in lower eukaryotes: relevance to the evolution and function of histones. J Mol Evol. 1976;8:79–94.

    Article  CAS  PubMed  Google Scholar 

  28. Luger K, Richmond TJ. The histone tails of the nucleosome. Curr Opin Genet Dev. 1998;8:140–6.

    Article  CAS  PubMed  Google Scholar 

  29. Copeland RA. Molecular pathways: protein methyltransferases in cancer. Clin Cancer Res. 2013;19:6344.

    Article  CAS  PubMed  Google Scholar 

  30. Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by Polycomb and Trithorax proteins. Cell. 2007;128:735–45.

    Article  CAS  PubMed  Google Scholar 

  31. Lomberk G, Bensi D, Fernandez-Zapico ME, Urrutia R. Evidence for the existence of an HP1-mediated subcode within the histone code. Nat Cell Biol. 2006;8:407–15.

    Article  CAS  PubMed  Google Scholar 

  32. Harouz H, Rachez C, Meijer BM, Marteyn B, Donnadieu F, Cammas F, Muchardt C, Sansonetti P, Arbibe L. Shigella flexneri targets the HP1γ subcode through the phosphothreonine lyase OspF. EMBO J. 2014;33:2606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Quénet D, Gasser V, Fouillen L, Cammas F, Sanglier-Cianferani S, Losson R, Dantzer F. The histone subcode: poly(ADP-ribose) polymerase-1 (Parp-1) and Parp-2 control cell differentiation by regulating the transcriptional intermediary factor TIF1β and the heterochromatin protein HP1α. FASEB J. 2008;22:3853–65.

    Article  PubMed  CAS  Google Scholar 

  34. Guo A, Gu H, Zhou J, Mulhern D, Wang Y, Lee KA, Yang V, Aguiar M, Kornhauser J, Jia X, et al. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol Cell Proteomics. 2014;13:372–87.

    Article  CAS  PubMed  Google Scholar 

  35. Zhang R, Chen W, Adams PD. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol. 2007;27:2343–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sampath SC, Marazzi I, Yap KL, Sampath SC, Krutchinsky AN, Mecklenbräuker I, Viale A, Rudensky E, Zhou M-M, Chait BT, et al. Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol Cell. 2007;27:596–608.

    Article  CAS  PubMed  Google Scholar 

  37. Lusser A, Kadonaga JT. Chromatin remodeling by ATP-dependent molecular machines. BioEssays. 2003;25:1192–200.

    Article  CAS  PubMed  Google Scholar 

  38. Kennison JA. The Polycomb and Trithorax group proteins of drosophila: trans-regulators of homeotic gene function. Annu Rev Genet. 1995;29:289–303.

    Article  CAS  PubMed  Google Scholar 

  39. Elfring LK, Deuring R, McCallum CM, Peterson CL, Tamkun JW. Identification and characterization of drosophila relatives of the yeast transcriptional activator SNF2/SWI2. Mol Cell Biol. 1994;14:2225–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chiba H, Muramatsu M, Nomoto A, Kato H. Two human homologues of Saccharomyces Cerevisiae SWI2/SNF2 and Drosophila Brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor. Nucleic Acids Res. 1994;22:1815–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wong AK. BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Res. 2000;60:6171–7.

    CAS  PubMed  Google Scholar 

  42. Wu Q, Lian JB, Stein JL, Stein GS, Nickerson JA, Imbalzano AN. The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics. 2017;9:919–31.

    Article  CAS  PubMed  Google Scholar 

  43. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–26.

    Article  CAS  PubMed  Google Scholar 

  44. Park Y-J, Luger K. Histone chaperones in nucleosome eviction and histone exchange. Curr Opin Struct Biol. 2008;18:282–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Loyola A, Almouzni G. Marking histone H3 variants: how, when and why? Trends Biochem Sci. 2007;32:425–33.

    Article  CAS  PubMed  Google Scholar 

  46. Hake SB, Allis CD. Histone H3 variants and their potential role in indexing mammalian genomes: the ‘H3 barcode hypothesis’. Proc Natl Acad Sci USA. 2006;103:6428–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Warren C, Shechter D. Fly fishing for histones: catch and release by histone chaperone intrinsically disordered regions and acidic stretches. J Mol Biol. 2017;429:2401–26.

    Article  CAS  PubMed  Google Scholar 

  48. Heard E, Bickmore W. The ins and outs of gene regulation and chromosome territory organisation. Curr Opin Cell Biol. 2007;19:311–6.

    Article  CAS  PubMed  Google Scholar 

  49. Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith ACM, Perry MB, Brewer CC, Zalewski C, Kim HJ, Solomon B, et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med. 2008;358:592–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gruenbaum Y, Wilson KL, Harel A, Goldberg M, Cohen M. Review: nuclear Lamins--structural proteins with fundamental functions. J Struct Biol. 2000;129:313–23.

    Article  CAS  PubMed  Google Scholar 

  51. Bell ES, Lammerding J. Causes and consequences of nuclear envelope alterations in tumour progression. Eur J Cell Biol. 2016;95:449–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Kloppel G, Longnecker DS, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001;25:579–86.

    Article  CAS  PubMed  Google Scholar 

  53. Lomberk GA, Urrutia R. The triple code model for pancreatic cancer: crosstalk among genetics, epigenetics, and nuclear structure. Surg Clin North Am. 2015;95:935–52.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.

    Article  CAS  PubMed  Google Scholar 

  55. Sato N, Maitra A, Fukushima N, van Heek NT, Matsubayashi H, Iacobuzio-Donahue CA, Rosty C, Goggins M. Frequent Hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res. 2003;63:4158–66.

    CAS  PubMed  Google Scholar 

  56. Ueki T, Toyota M, Skinner H, Walter KM, Yeo CJ, Issa J-PJ, Hruban RH, Goggins M. Identification and characterization of differentially methylated CpG Islands in pancreatic carcinoma. Cancer Res. 2001;61:8540–6.

    CAS  PubMed  Google Scholar 

  57. Ueki T, Toyota M, Sohn T, Yeo CJ, Issa J-PJ, Hruban RH, Goggins M. Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res. 2000;60:1835–9.

    CAS  PubMed  Google Scholar 

  58. Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer. 2007;7:654–8.

    Article  CAS  Google Scholar 

  59. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–59.

    Article  CAS  PubMed  Google Scholar 

  60. Singh M, Maitra A. Precursor lesions of pancreatic cancer: molecular pathology and clinical implications. Pancreatology. 2007;7:9–19. Epub 2007 Apr 2018

    Article  CAS  PubMed  Google Scholar 

  61. Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, Billadeau DD. Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis. Cancer Cell. 2005;7:39–49.

    Article  CAS  PubMed  Google Scholar 

  62. Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M. p16 inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol. 2003;27:1495–501.

    Article  PubMed  Google Scholar 

  63. Sato N, Fukushima N, Maitra A, Matsubayashi H, Yeo CJ, Cameron JL, Hruban RH, Goggins M. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res. 2003;63:3735–42.

    CAS  PubMed  Google Scholar 

  64. Zhao Y, Sun J, Zhang H, Guo S, Gu J, Wang W, Tang N, Zhou X, Yu J. High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq. Clin Epigenetics. 2014;6:18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Vincent A, Omura N, Hong S-M, Jaffe A, Eshleman J, Goggins M. Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin Cancer Res. 2011;17:4341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kisiel JB, Raimondo M, Taylor WR, Yab TC, Mahoney DW, Sun Z, Middha S, Baheti S, Zou H, Smyrk TC, et al. New DNA methylation markers for pancreatic cancer: discovery, tissue validation, and pilot testing in pancreatic juice. Clin Cancer Res. 2015;21:4473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Henriksen SD, Madsen PH, Larsen AC, Johansen MB, Drewes AM, Pedersen IS, Krarup H, Thorlacius-Ussing O. Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma. Clin Epigenetics. 2016;8:117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Allis C, Jenuwein T, Reinberg D, Capparros ML, editors. Epigenetics, 1st edition. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2007.

    Google Scholar 

  69. Privalsky M, editor. Transcriptional corepressors: mediators of eukaryotic gene expression, volume 254. New York: Springer-Verlag; 2001.

    Google Scholar 

  70. Cress W, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell Physiol. 2000;184:1–16.

    Article  CAS  PubMed  Google Scholar 

  71. Blasco F, Peñuelas S, Cascalló M, Hernández JL, Alemany C, Masa M, Calbó J, Soler M, Nicolás M, Pérez-Torras S, et al. Expression profiles of a human pancreatic cancer cell line upon induction of apoptosis search for modulators in cancer therapy. Oncology. 2004;67:277–90.

    Article  CAS  PubMed  Google Scholar 

  72. Ouaïssi M, Sielezneff I, Silvestre R, Sastre B, Bernard J-P, Lafontaine J, Payan M, Dahan L, Pirrò N, Seitz J, et al. High histone deacetylase 7 (HDAC7) expression is significantly associated with adenocarcinomas of the pancreas. Ann Surg Oncol. 2008;15:2318–28.

    Article  PubMed  Google Scholar 

  73. Giaginis C, Damaskos C, Koutsounas I, Zizi-Serbetzoglou A, Tsoukalas N, Patsouris E, Kouraklis G, Theocharis S. Histone deacetylase (HDAC)-1, −2, −4 and −6 expression in human pancreatic adenocarcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients’ survival. BMC Gastroenterol. 2015;15:148.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Zhao S, Venkatasubbarao K, Li S, Freeman JW. Requirement of a specific Sp1 site for histone deacetylase-mediated repression of transforming growth factor {beta} type II receptor expression in human pancreatic cancer cells. Cancer Res. 2003;63:2624–30.

    CAS  PubMed  Google Scholar 

  75. Truty MJ, Lomberk G, Fernandez-Zapico ME, Urrutia R. Silencing of the TGFbeta receptor II by kruppel-like factor 14 underscores the importance of a negative feedback mechanism in TGFbeta signaling. J Biol Chem. 2008. https://doi.org/10.1074/jbc.M807791200.

  76. Lomberk G, Zhang J, Truty M, Urrutia R. A new molecular model for regulating the TGF[beta] receptor II promoter in pancreatic cells. Pancreas. 2008;36:222–3.

    Article  Google Scholar 

  77. Wolpin BM, Rizzato C, Kraft P, Kooperberg C, Petersen GM, Wang Z, Arslan AA, Beane-Freeman L, Bracci PM, Buring J, et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet. 2014;46:994–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Edderkaoui M, Xu S, Chheda C, Morvaridi S, Hu RW, Grippo PJ, Mascariñas E, Principe DR, Knudsen B, Xue J, et al. HDAC3 mediates smoking-induced pancreatic cancer. Oncotarget. 2016;7:7747–60.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Tchio Mantho CI, Harbuzariu A, Gonzalez-Perez RR. Histone deacetylases, microRNA and leptin crosstalk in pancreatic cancer. World Journal of Clinical Oncology. 2017;8:178–89.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–43.

    Article  CAS  PubMed  Google Scholar 

  81. Grzenda AL, Lomberk G, Urrutia R. Different EZH2 isoforms are expressed in pancreatic cells: evidence for a polycomb-mediated subcode within the context of the histone code. Pancreas. 2007;35:404.

    Article  Google Scholar 

  82. Wei Y, Xia W, Zhang Z, Liu J, Wang H, Adsay N, Albarracin C, Yu D, Abbruzzese J, Mills G, et al. Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers. Mol Carcinog. 2008;47:701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ougolkov AV, Bilim VN, Billadeau DD. Regulation of pancreatic tumor cell proliferation and Chemoresistance by the histone methyltransferase enhancer of Zeste homologue 2. Clin Cancer Res. 2008;14:6790–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gao L, Antic T, Hyjek E, Gong C, Mueller J, Waxman I, DeMay RM, Reeves W. Immunohistochemical analysis of E-cadherin and zeste homolog 2 expression in endoscopic ultrasound-guided fine-needle aspiration of pancreatic adenocarcinoma. Cancer Cytopathol. 2013;121:644–52.

    Article  PubMed  Google Scholar 

  85. Mallen-St. Clair J, Soydaner-Azeloglu R, Lee KE, Taylor L, Livanos A, Pylayeva-Gupta Y, Miller G, Margueron R, Reinberg D, Bar-Sagi D. EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev. 2012;26:439–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Jin X, Yang C, Fan P, Xiao J, Zhang W, Zhan S, Liu T, Wang D, Wu H. CDK5/FBW7-dependent ubiquitination and degradation of EZH2 inhibits pancreatic cancer cell migration and invasion. J Biol Chem. 2017;292:6269–80.

    Article  CAS  PubMed  Google Scholar 

  87. Chen J, Xu H, Zou X, Wang J, Zhu Y, Chen H, Shen B, Deng X, Zhou A, Chin YE, et al. Snail recruits Ring1B to mediate transcriptional repression and cell migration in pancreatic cancer cells. Cancer Res. 2014;74:4353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Karamitopoulou E, Pallante P, Zlobec I, Tornillo L, Carafa V, Schaffner T, Borner M, Diamantis I, Esposito F, Brunner T, et al. Loss of the CBX7 protein expression correlates with a more aggressive phenotype in pancreatic cancer. Eur J Cancer. 2010;46:1438–44.

    Article  CAS  PubMed  Google Scholar 

  89. Ni S, Wang H, Zhu X, Wan C, Xu J, Lu C, Xiao L, He J, Jiang C, Wang W, et al. CBX7 suppresses cell proliferation, migration, and invasion through the inhibition of PTEN/Akt signaling in pancreatic cancer. Oncotarget. 2017;8:8010–21.

    PubMed  Google Scholar 

  90. Proctor E, Waghray M, Lee CJ, Heidt DG, Yalamanchili M, Li C, Bednar F, Simeone DM. Bmi1 enhances Tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma. PLoS One. 2013;8:e55820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang M-C, Jiao M, Wu T, Jing L, Cui J, Guo H, Tian T, Ruan Z-p, Wei Y-C, Jiang L-L, et al. Polycomb complex protein BMI-1 promotes invasion and metastasis of pancreatic cancer stem cells by activating PI3K/AKT signaling, an ex vivo, in vitro, and in vivo study. Oncotarget. 2016;7:9586–99.

    PubMed  PubMed Central  Google Scholar 

  92. Bednar F, Schofield HK, Collins MA, Yan W, Zhang Y, Shyam N, Eberle JA, Almada LL, Olive KP, Bardeesy N, et al. Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism. Carcinogenesis. 2015;36:730–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4a tumor suppressor gene. Genes Dev. 2007;21:49–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden J-M, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–4.

    Article  CAS  PubMed  Google Scholar 

  95. Lomberk G, Wallrath L, Urrutia R. The heterochromatin protein 1 family. Genome Biol. 2006;7:228.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Dialynas GK, Vitalini MW, Wallrath LL. Linking heterochromatin protein 1 (HP1) to cancer progression. Mutat Res. 2008;647:13–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Masaki Y, Oka M, Ogura Y, Ueno T, Nishihara K, Tangoku A, Takahashi M, Yamamoto M, Irimura T. Sialylated MUC1 mucin expression in normal pancreas, benign pancreatic lesions, and pancreatic ductal adenocarcinoma. Hepato-Gastroenterology. 1999;46:2240–5.

    CAS  PubMed  Google Scholar 

  98. Mukherjee P, Basu GD, Tinder TL, Subramani DB, Bradley JM, Arefayene M, Skaar T, De Petris G. Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition. J Immunol. 2009;182:216–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yamada N, Nishida Y, Tsutsumida H, Hamada T, Goto M, Higashi M, Nomoto M, Yonezawa S. MUC1 expression is regulated by DNA methylation and histone H3 lysine 9 modification in cancer cells. Cancer Res. 2008;68:2708–16.

    Article  CAS  PubMed  Google Scholar 

  100. Smallwood A, Esteve P-O, Pradhan S, Carey M. Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev. 2007;21:1169–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Baumgart S, Glesel E, Singh G, Chen N-M, Reutlinger K, Zhang J, Billadeau DD, Fernandez-Zapico ME, Gress TM, Singh SK, et al. Restricted heterochromatin formation links NFATc2 repressor activity with growth promotion in pancreatic cancer. Gastroenterology. 2012;142:388–98. e381-387

    Article  CAS  PubMed  Google Scholar 

  102. McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, Word AE, Carrer A, Salz TH, Natsume S, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017;49:367–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yuan Y, Wang Q, Paulk J, Kubicek S, Kemp MM, Adams DJ, Shamji AF, Wagner BK, Schreiber SL. A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem Biol. 2012;7:1152–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mathison A, Salmonson A, Missfeldt M, Bintz J, Williams M, Kossak S, Nair A, de Assuncao TM, Christensen T, Buttar N, et al. Combined AURKA and H3K9 methyltransferase targeting inhibits cell growth by inducing mitotic catastrophe. In: Molecular cancer research; 2017.

    Google Scholar 

  105. Lomberk G, Urrutia R. The family feud: turning off Sp1 by Sp1-like KLF proteins. Biochem J. 2005;392:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Waddell N, Pajic M, Patch A-M, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yamamoto K, Tateishi K, Kudo Y, Sato T, Yamamoto S, Miyabayashi K, Matsusaka K, Asaoka Y, Ijichi H, Hirata Y, et al. Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. Carcinogenesis. 2014;35:2404–14.

    Article  CAS  PubMed  Google Scholar 

  108. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008;9:102–14.

    Article  CAS  PubMed  Google Scholar 

  109. Lee E, Gusev Y, Jiang J, Nuovo G, Lerner M, Frankel W, Morgan D, Postier R, Brackett D, Schmittgen T. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer. 2007;120:1046–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Szafranska AE, Davison TS, John J, Cannon T, Sipos B, Maghnouj A, Labourier E, Hahn SA. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 2007;26:4442–52.

    Article  CAS  PubMed  Google Scholar 

  111. Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, Liu C-G, Bhatt D, Taccioli C, Croce CM. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–8.

    Article  CAS  PubMed  Google Scholar 

  112. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105:10513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Xu J, Cao Z, Liu W, You L, Zhou L, Wang C, Lou W, Sun B, Miao Y, Liu X, et al. Plasma miRNAs effectively distinguish patients with pancreatic cancer from controls: a Multicenter study. Ann Surg. 2016;263:1173–9.

    Article  PubMed  Google Scholar 

  114. Pei Z, Liu S-M, Huang J-T, Zhang X, Yan D, Xia Q, Ji C, Chen W, Zhang X, Xu J, et al. Clinically relevant circulating microRNA profiling studies in pancreatic cancer using meta-analysis. Oncotarget. 2017;8:22616–24.

    PubMed  PubMed Central  Google Scholar 

  115. Franklin O, Jonsson P, Billing O, Lundberg E, Öhlund D, Nyström H, Lundin C, Antti H, Sund M. Plasma micro-RNA alterations appear late in pancreatic cancer. Annals of Surgery. 2017. https://doi.org/10.1097/SLA.0000000000002124.

  116. Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136:629–41.

    Article  CAS  PubMed  Google Scholar 

  117. Peng J-F, Zhuang Y-Y, Huang F-T, Zhang S-N. Noncoding RNAs and pancreatic cancer. World J Gastroenterol. 2016;22:801–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Work in the authors’ laboratories is supported by NIH DK52913 (to RU), NIH CA178627 (to GL), ChiRhoClin, Research Institute (to RU and GL), as well as the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701).

Author information

Authors and Affiliations

  1. Division of Research, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd, TBRC, C4860, Milwaukee, WI, 53226, USA

    Gwen Lomberk

  2. Division of Research, Department of Surgery and Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA

    Raul Urrutia

Authors
  1. Gwen Lomberk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raul Urrutia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gwen Lomberk .

Editor information

Editors and Affiliations

  1. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    John P. Neoptolemos

  2. Division of Research Department of Surgery and Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Raul Urrutia

  3. Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA

    James L. Abbruzzese

  4. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    Markus W. Büchler

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC, part of Springer Nature

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Lomberk, G., Urrutia, R. (2018). Epigenetics and Its Applications to the Progression Model of Pancreatic Cancer. In: Neoptolemos, J., Urrutia, R., Abbruzzese, J., Büchler, M. (eds) Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7193-0_6

Download citation

Publish with us

Policies and ethics

Search

Navigation