1932

Abstract

The reprogramming of the epigenome through silencing of genes and microRNAs by cytosine DNA methylation and chromatin remodeling is critical for the initiation and progression of lung cancer through affecting all major cell regulatory pathways. Importantly, the fact that epigenetic reprogramming is reversible by pharmacological agents has opened new avenues for clinical intervention. This review focuses on the tremendous progress made in elucidating genes and microRNAs that are epigenetically silenced in lung cancer and highlights how loss of function impacts cell phenotype and major signaling pathways. The article describes the utility of () an in vitro model using hTERT/Cdk4 immortalized human bronchial epithelial cell lines to identify genes and microRNAs silenced during premalignancy and () an in vivo orthotopic nude rat lung cancer model to evaluate response to epigenetic therapy. New insights regarding the advantage of aerosol delivery of demethylating agents and the concept of priming tumors for subsequent therapy are presented and discussed.

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2015-02-10
2024-12-14
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Literature Cited

  1. Siegel R, Ma J, Zou Z, Jemal A. 1.  2014. Cancer statistics. CA Cancer J. Clin. 64:9–29 [Google Scholar]
  2. Hecht SS. 2.  2008. Progress and challenges in selected areas of tobacco carcinogenesis. Chem. Res. Toxicol. 21:160–71 [Google Scholar]
  3. Slaughter DP, Southwick HW, Smejkal W. 3.  1953. “Field cancerization” in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 5:963–68 [Google Scholar]
  4. Auerbach O, Hammond EC, Garfinkel L. 4.  1979. Changes in bronchial epithelium in relation to cigarette smoking, 1955–1960 versus 1970–1977. N. Engl. J. Med. 300:381–85 [Google Scholar]
  5. Belinsky SA, Palmisano WA, Gilliland FD, Crooks LA, Divine KK. 5.  et al. 2002. Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res. 62:2370–77 [Google Scholar]
  6. Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM. 6.  1997. Clonal genetic alterations in the lungs of current and former smokers. J. Natl. Cancer Inst. 89:834–36 [Google Scholar]
  7. Bunn PA Jr, Franklin W, Doebele RC. 7.  2013. The evolution of tumor classification: a role for genomics?. Cancer Cell 24:693–94 [Google Scholar]
  8. Riessk J. 8.  2013. Shifting paradigms in non–small cell lung cancer: an evolving therapeutic landscape. Am. J. Manag. Care 19:390–97 [Google Scholar]
  9. Timp W, Feinberg AP. 9.  2013. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat. Rev. Cancer 13:497–10 [Google Scholar]
  10. Hanahan D, Weinberg RA. 10.  2011. Hallmarks of cancer: the next generation. Cell 144:646–74 [Google Scholar]
  11. Gardiner-Garden M, Frommer M. 11.  1987. CpG islands in vertebrate genomes. J. Mol. Biol. 196:261–82 [Google Scholar]
  12. Bestor TH. 12.  2000. The DNA methyltransferases of mammals. Hum. Mol. Genet. 9:2395–402 [Google Scholar]
  13. McCade MT, Brandes JC, Vertino PM. 13.  2009. Cancer DNA methylation: molecular mechanisms and clinical implications. Clin. Cancer Res. 15:3927–37 [Google Scholar]
  14. Ting AH, McGarvey KM, Baylin SB. 14.  2006. The cancer epigenome—components and functional correlates. Genes Dev. 20:3215–31 [Google Scholar]
  15. Jones PA, Baylin SB. 15.  2007. The epigenomics of cancer. Cell 128:683–92 [Google Scholar]
  16. Albert M, Helin K. 16.  2010. Histone methyltransferases in cancer. Semin. Cell Dev. Biol. 21:209–20 [Google Scholar]
  17. Breuer RHJ, Snijders PJF, Smit EF, Sutedja TG, Sewalt RGAB. 17.  et al. 2004. Increased expression of the EZH2 polycomb group gene in BMI-1-positive neoplastic cells during bronchial carcinogenesis. Neoplasia 6:736–43 [Google Scholar]
  18. Watanabe H, Soejima K, Yasuda HY, Kawada I, Nakachi I. 18.  et al. 2008. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell Int. 8:15 [Google Scholar]
  19. Chen MW, Hua KT, Kao HJ, Chi CC, Wei LH. 19.  et al. 2010. H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 70:7830–40 [Google Scholar]
  20. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M. 20.  et al. 2007. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet. 39:232–36 [Google Scholar]
  21. Gal-Yam EM, Egger G, Iniguez L, Holster H, Einarsson S. 21.  et al. 2008. Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc. Natl. Acad. Sci. USA 105:12979–84 [Google Scholar]
  22. Jin B, Yao B, Li J-L, Fields CR, Delmas AL. 22.  et al. 2009. DNMT1 and DNMT3B modulate distinct polycomb-mediated histone modifications in colon cancer. Cancer Res. 69:7412–21 [Google Scholar]
  23. Viré E, Brenner C, Deplus R, Blanchon L, Fraga M. 23.  et al. 2006. The polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–74 [Google Scholar]
  24. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS. 24.  et al. 2006. Control of developmental regulators by polycomb in human embryonic stem cells. Cell 125:301–13 [Google Scholar]
  25. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G. 25.  et al. 2007. Epigenetic stem cell signature in cancer. Nat. Genet. 39:157–58 [Google Scholar]
  26. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE. 26.  et al. 2007. A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat. Genet. 39:237–42 [Google Scholar]
  27. Tachibana M, Matsumura Y, Fukuda M, Kimura H, Shinkai Y. 27.  2008. G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO J. 27:2681–90 [Google Scholar]
  28. Serrano M, Hannon GJ, Beach D. 28.  1993. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 16:704–7 [Google Scholar]
  29. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K. 29.  et al. 1994. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–40 [Google Scholar]
  30. Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E. 30.  et al. 1995. 5′CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat. Med. 1:633–34 [Google Scholar]
  31. Zöchbauer-Müller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD. 31.  2001. Aberrant promoter methylation of multiple genes in non–small cell lung cancers. Cancer Res. 61:249–55 [Google Scholar]
  32. Kim D-H, Nelson HH, Wiencke JK, Zheng S, Christiani DC. 32.  et al. 2001. p16INK4a and histology-specific methylation of CpG islands by exposure to tobacco smoke in non–small cell lung cancer. Cancer Res. 61:3419–24 [Google Scholar]
  33. Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G. 33.  et al. 1998. Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proc. Natl. Acad. Sci. USA 95:11891–96 [Google Scholar]
  34. Lukas J, Parry D, Aaqaard L, Mann DJ, Bartkova J. 34.  et al. 1995. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16. Nature 375:503–6 [Google Scholar]
  35. Weinberg RA. 35.  1995. The retinoblastoma protein and cell cycle control. Cell 81:323–30 [Google Scholar]
  36. Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ. 36.  1988. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241:353–57 [Google Scholar]
  37. Foster SA, Wong DJ, Barrett MT, Galloway DA. 37.  1998. Inactivation of p16 in human mammary epithelial cells by CpG island methylation. Mol. Cell. Biol. 18:1793–801 [Google Scholar]
  38. Wong DJ, Foster SA, Galloway DA, Reid BJ. 38.  1999. Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M0 growth arrest. Mol. Cell. Biol. 19:5642–51 [Google Scholar]
  39. Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB. 39.  1996. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl. Acad. Sci. USA 93:9821–26 [Google Scholar]
  40. Licchesi JD, Westra WH, Hooker CM, Heman JG. 40.  2008. Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung. Clin. Cancer Res. 14:2570–78 [Google Scholar]
  41. Pulling LC, Divine KK, Klinge DM, Gilliland FD, Kang T. 41.  et al. 2003. Promoter hypermethylation of the O6-methylguanine-DNA methyltransferase gene: more common in lung adenocarcinomas from never-smokers than smokers and associated with tumor progression. Cancer Res. 64:4742–48 [Google Scholar]
  42. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. 42.  1999. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 59:793–97 [Google Scholar]
  43. Furonaka O, Takeshima Y, Aways H, Kushitani K, Kohno N, Inai K. 43.  2005. Aberrant methylation and loss of expression of O6-methylguanine-DNA methyltransferase in pulmonary squamous cell carcinoma and adenocarcinoma. Pathol. Int. 55:303–9 [Google Scholar]
  44. Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA. 44.  et al. 2000. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res. 60:2368–71 [Google Scholar]
  45. Yin D, Xie D, Hofmann WK, Zhang W, Asotra K. 45.  et al. 2003. DNA repair gene O6-methylguanine-DNA methyltransferase: promoter hypermethylation associated with decreased expression and G:C to A:T mutations of p53 in brain tumors. Mol. Carcinog. 36:23–31 [Google Scholar]
  46. Gomes A, Reis-Silva M, Alarcão A, Couceiro P, Sousa V, Carvalho L. 46.  2014. Promoter hypermethylation of DNA repair genes MLH1 and MSH2 in adenocarcinomas and squamous cell carcinomas of the lung. Rev. Port. Pneumol. 20:20–30 [Google Scholar]
  47. Cohen O, Feinstein E, Kimchi A. 47.  1997. DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death–inducing functions that depend on its catalytic activity. EMBO J. 16:998–108 [Google Scholar]
  48. Cohen O, Inbal B, Kissil JL, Raveh T, Berissi H. 48.  et al. 1999. DAP-kinase participates in TNF-α and Fas-induced apoptosis and its function requires the death domain. J. Cell Biol. 146:141–48 [Google Scholar]
  49. Tang X, Khuri FR, Lee JJ, Kemp BL, Liu D. 49.  et al. 2000. Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non–small cell lung cancer. J. Natl. Cancer Inst. 92:1511–16 [Google Scholar]
  50. Kim DH, Nelson HH, Wiencke JK, Christiani DC, Wain JC. 50.  et al. 2001. Promoter methylation of DAP-kinase: association with advanced stage in non–small cell lung cancer. Oncogene 20:1765–70 [Google Scholar]
  51. Toyooka A, Toyooka KO, Miyajima K, Reddy JL, Toyota M. 51.  et al. 2003. Epigenetic down-regulation of death-associated protein kinase in lung cancers. Clin. Cancer Res. 9:3034–41 [Google Scholar]
  52. Raveh T, Drouguett G, Horwitz MS, DePinho RA, Kimchi A. 52.  et al. 2001. DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat. Cell Biol. 3:1–7 [Google Scholar]
  53. Shivapurkar N, Toyooka S, Eby MT, Huang CX, Sathyanarayana UG. 53.  et al. 2002. Differential inactivation of caspase-8 in lung cancers. Cancer Biol. Ther. 1:65–69 [Google Scholar]
  54. Hopkins-Donaldson S, Ziegler A, Kurtz S, Bigosch C, Kandioler D. 54.  et al. 2003. Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ. 10:356–64 [Google Scholar]
  55. Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ. 55.  1998. Increasing complexity of Ras signaling. Oncogene 17:1395–413 [Google Scholar]
  56. Downward J. 56.  2001. The ins and outs of signaling. Nature 411:759–62 [Google Scholar]
  57. Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP. 57.  2000. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat. Genet. 25:315–19 [Google Scholar]
  58. Burbee DG, Forqacs E, Zöchbauer-Müller S, Shivakumar L, Fong K. 58.  et al. 2001. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J. Natl. Cancer Inst. 93:691–99 [Google Scholar]
  59. Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T. 59.  et al. 2002. Identification of a novel Ras-regulated proapoptotic pathway. Curr. Biol. 12:253–65 [Google Scholar]
  60. Hesson L, Dallol A, Minna JD, Maher ER, Latif F. 60.  2003. NORE1A, a homologue of RASSF1A tumour suppressor gene is inactivated in human cancers. Oncogene 22:947–54 [Google Scholar]
  61. Thaler S, Hahnel PS, Schad A, Dammann R, Schuler M. 61.  2009. RASSF1A mediates p21Cip1/Waf1-dependent cell cycle arrest and senescence through modulation of the Raf-MEK-ERK pathway and inhibition of Akt. Cancer Res. 59:1748–57 [Google Scholar]
  62. Takeichi M. 62.  1991. Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251:1451–55 [Google Scholar]
  63. Chambers AF, Matrisian LM. 63.  1997. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer Inst. 89:1260–70 [Google Scholar]
  64. Colognato H, Yurchenco PD. 64.  2000. Form and function: the laminin family of heterotrimers. Dev. Dyn. 218:213–34 [Google Scholar]
  65. Giannelli G, Antonaci S. 65.  2000. Biological and clinical relevance of laminin-5 in cancer. Clin. Exp. Metastasis 18:439–43 [Google Scholar]
  66. Toyooka KO, Toyooka S, Virmani AK, Sathyanarayana UG, Euhus DM. 66.  et al. 2001. Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas. Cancer Res. 6:4556–60 [Google Scholar]
  67. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A. 67.  et al. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:404–15 [Google Scholar]
  68. Polyak K, Weinberg RA. 68.  2009. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9:265–73 [Google Scholar]
  69. Bachman KE, Herman JG, Corn PG, Merlo A, Costello JF. 69.  et al. 1999. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggests a suppressor role in kidney, brain, and other human cancers. Cancer Res. 59:798–802 [Google Scholar]
  70. Sathyanarayana UB, Toyooka S, Padar A, Takahashi T, Brambilla E. 70.  et al. 2003. Epigenetic inactivation of laminin-5-encoding genes in lung cancers. Clin. Cancer Res. 9:2665–72 [Google Scholar]
  71. Kikuchi S, Yamada D, Fukami T, Masuda M, Sakurai-Yageta M. 71.  et al. 2005. Promoter methylation of DAL-1/4.1B predicts poor prognosis in non–small cell lung cancer. Clin. Cancer Res. 11:2954–61 [Google Scholar]
  72. Heller G, Fong KM, Girard L, Seidi S, End-Pfutzenreuter A. 72.  et al. 2006. Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas. Oncogene 25:959–68 [Google Scholar]
  73. Korinek V, Barker N, Morin PJ, Van Wichen D, de Weger R. 73.  et al. 1997. Constitutive transcriptional activation by a β-catenin–Tcf complex in APC−/− colon carcinoma. Science 275:1784–87 [Google Scholar]
  74. Morin PJ, Sparks AB, Lorinek V, Barker N, Clevers H. 74.  et al. 1997. Activation of β-catenin–Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275:1787–90 [Google Scholar]
  75. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. 75.  et al. 1998. Mutational analysis of the APC/β-catenin/Tcf pathway in colorectal cancer. Cancer Res. 58:1130–34 [Google Scholar]
  76. Licchesi JD, Westra WH, Hooker CM, Achida EO, Baylin SB, Herman JG. 76.  2008. Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. Carcinogenesis 29:895–904 [Google Scholar]
  77. Fukui T, Kondo M, Ito G, Maeda O, Sata N. 77.  et al. 2005. Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene 24:6323–27 [Google Scholar]
  78. Mazieres J, He B, You L, Xu Z, Lee AY. 78.  et al. 2004. Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer. Cancer Res. 64:4717–20 [Google Scholar]
  79. Guo M, Akiyama Y, House MG, Hooker CM, Heath E. 79.  et al. 2004. Hypermethylation of the GATA genes in lung cancer. Clin. Cancer Res. 10:7917–24 [Google Scholar]
  80. Akiyama Y, Watkins N, Suzuki H, Jair KW, van Engeland M. 80.  et al. 2003. GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer. Mol. Cell. Biol. 23:8429–39 [Google Scholar]
  81. Busslinger M, Klix N, Pfeffer P, Graninger PG, Kozmik Z. 81.  1996. Deregulation of PAX-5 by translocation of the Eμ enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma. Proc. Natl. Acad. Sci. USA 93:6129–34 [Google Scholar]
  82. Palmisano WA, Crume KP, Grimes MJ, Winters SA, Toyota M. 82.  et al. 2003. Aberrant promoter methylation of the transcription factor genes PAX5 α and β in human cancers. Cancer Res. 63:4620–25 [Google Scholar]
  83. Kozmik Z, Wang S, Dorfler P, Adams B, Busslinger M. 83.  1992. The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP. Mol. Cell. Biol. 12:2662–72 [Google Scholar]
  84. Tessema M, Yu YY, Stidely CA, Machida EO, Schuebel KE, Baylin SB. 84.  2009. Concomitant promoter methylation of multiple genes in lung adenocarcinomas from current, former and never smokers. Carcinogenesis 30:1132–38 [Google Scholar]
  85. Hsu HK, Weng YI, Hsu PY, Huang TH, Huang YW. 85.  2014. Detection of DNA methylation by MeDIP and MBDCap assays: an overview of techniques. Methods Mol. Biol. 1105:61–70 [Google Scholar]
  86. Estécio MR, Yan PS, Ibrahim AE, Tellez CS, Shen L. 86.  et al. 2007. High-throughput methylation profiling by MCA coupled to CpG island microarray. Genome Res. 17:1529–36 [Google Scholar]
  87. Kalari S, Jung M, Kernstine KH, Takahashi T, Pfeifer GP. 87.  2013. The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cells. Oncogene 32:3559–68 [Google Scholar]
  88. Schuebel KE, Chen W, Cope L, Glöckner SC, Suzuki H. 88.  et al. 2007. Comparing the DNA hypermeth-ylome with gene mutations in human colorectal cancer. PLoS Genet. 3:1709–23 [Google Scholar]
  89. Tessema M, Yingling CM, Liu Y, Tellez CS, Van Neste L. 89.  et al. 2014. Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers. Carcinogenesis 351248–57 [Google Scholar]
  90. Tessema M, Klinge DM, Yingling CM, Do K, Van Neste L, Belinsky SA. 90.  2010. Re-expression of the CXCL14 chemokine, a common target for epigenetic silencing in lung cancer, induces tumor necrosis. Oncogene 29:5159–70 [Google Scholar]
  91. Naeem H, Wong NC, Chatterton Z, Hong MK, Pedersen JS. 91.  et al. 2014. Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array. BMC Genomics 15:51 [Google Scholar]
  92. Sato T, Aral E, Kohno T, Tsuta K, Watanabe S. 92.  et al. 2013. DNA methylation profiles at precancerous stages associated with recurrence of lung adenocarcinoma. PLoS ONE 8:e59444 [Google Scholar]
  93. Sandoval J, Mendez-Gonzalez J, Nadal E, Chen G, Carmona FJ. 93.  et al. 2013. A prognostic DNA methylation signature for stage I non–small-cell lung cancer. J. Clin. Oncol. 31:4140–47 [Google Scholar]
  94. Darash-Yahana M, Gillespie JW, Hewitt SM, Chen YY, Maeda S. 94.  et al. 2009. The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers. PLoS ONE 4:e6695 [Google Scholar]
  95. Hromas R, Broxmeyer HE, Kim C, Nakshatri H, Christopherson K 2nd. 95.  et al. 1999. Cloning of BRAK, a novel divergent CXC chemokine preferentially expressed in normal versus malignant cells. Biochem. Biophys. Res. Commun. 255:703–6 [Google Scholar]
  96. Mu X, Chen Y, Wang S, Huang X, Pan H, Li M. 96.  2009. Overexpression of VCC-1 gene in human hepatocellular carcinoma cells promotes cell proliferation and invasion. Acta Biochim. Biophys. Sin. 41:631–37 [Google Scholar]
  97. Strieter RM, Belperio JA, Burdick MD, Sharma S, Dubinett SM, Keane MP. 97.  2004. CXC chemokines: angiogenesis, immunoangiostasis, and metastases in lung cancer. Ann. N. Y. Acad. Sci. 1028:351–60 [Google Scholar]
  98. Shellenberger TD, Wang M, Gujrati M, Jayakumar A, Strieter RM. 98.  et al. 2004. BRAK/CXCL14 is a potent inhibitor of angiogenesis and a chemotactic factor for immature dendritic cells. Cancer Res. 64:8262–70 [Google Scholar]
  99. Shurin GV, Ferris RL, Tourkova IL, Perez L, Lokshin A. 99.  et al. 2005. Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. J. Immunol. 174:5490–98 [Google Scholar]
  100. Teneng I, Tellez CS, Picchi MA, Klinge DM, Yingling CM. 100.  et al. 2014. Global identification of genes targeted by DNMT3b for epigenetic silencing in lung cancer. Oncogene In press [Google Scholar]
  101. Ozsolak F, Poling LL, Wang Z, Liu H, Liu XS. 101.  et al. 2008. Chromatin structure analyses identify miRNA promoters. Genes Dev. 22:3172–83 [Google Scholar]
  102. He L, Hannon GJ. 102.  2004. MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet. 5:522–31 [Google Scholar]
  103. Heller G, Weinzierl M, Noll C, Babinsky V, Ziegler B. 103.  et al. 2012. Genome-wide miRNA expression profiling identifies miR-9-3 and miR-193a as targets for DNA methylation in non–small cell lung cancers. Clin. Cancer Res. 18:1619–29 [Google Scholar]
  104. Watanabe K, Emoto N, Hamano E, Sunohara M, Kawakami M. 104.  et al. 2012. Genome structure–based screening identified epigenetically silenced microRNA associated with invasiveness in non-small-cell lung cancer. Int. J. Cancer 130:2580–90 [Google Scholar]
  105. Corney DC, Fleskin-Niktin A, Godwin AK, Wang W, Niktin AY. 105.  2007. MicroRNA-34b and microRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Res. 67:8433–38 [Google Scholar]
  106. Nadal E, Chen G, Gallegos M, Lin L, Ferrer-Torres D. 106.  2013. Epigenetic inactivation of microRNA-34b/c predicts poor disease-free survival in early-stage lung adenocarcinoma. Clin. Cancer Res. 19:6842–52 [Google Scholar]
  107. Xi S, Xu H, Shan J, Tao Y, Hong JA. 107.  2013. Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis. J. Clin. Investig. 123:1241–61 [Google Scholar]
  108. Rykov SV, Khodyrev DS, Pronina IV, Kazubskaya TP, Loginov VI, Braga EA. 108.  2013. Novel miRNA genes methylated in lung tumors. Genetika 49:896–901 [Google Scholar]
  109. Tan W, Gu J, Huang M, Wu X, Hildebrandt MA. 109.  2014. Epigenetic analysis of microRNA genes in tumors from surgically resected lung cancer patients and association with survival. Mol. Carcinog. In press [Google Scholar]
  110. Lujambio A, Esteller M. 110.  2007. CpG island hypermethylation of tumor suppressor microRNAs in human cancer. Cell Cycle 6:1455–59 [Google Scholar]
  111. Zhu X, Li Y, Shen H, Li H, Long L, Hui L. 111.  2013. miR-137 inhibits the proliferation of lung cancer cells by targeting Cdc42 and Cdk6. FEBS Lett. 587:73–81 [Google Scholar]
  112. Cao J, Song Y, Bi N, Shen J, Liu W. 112.  et al. 2013. DNA methylation–mediated repression of miR-886-3p predicts poor outcome of human small cell lung cancer. Cancer Res. 73:3326–35 [Google Scholar]
  113. Li N, Zhang F, Li S, Zhou S. 113.  2014. Epigenetic silencing of microRNA-503 regulates FANCA expression in non–small cell lung cancer cell. Biochem. Biophys. Res. Commun. 444:611–16 [Google Scholar]
  114. Damiani LA, Yingling CM, Leng S, Romo PE, Nakamura J, Belinsky SA. 114.  2008. Carcinogen-induced gene promoter hypermethylation is mediated by DNMT1 and causal for transformation of immortalized bronchial epithelial cells. Cancer Res. 68:9005–14 [Google Scholar]
  115. Ramirez RD, Sheridan S, Girard L, Sato M, Kim Y. 115.  et al. 2004. Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins. Cancer Res. 64:9027–34 [Google Scholar]
  116. Tellez CS, Juri DE, Do K, Bernauer AM, Thomas CL. 116.  et al. 2011. Carcinogen exposure induces EMT through epigenetic silencing of miR-205 and miR-200 family and promotes stem-like phenotype during transformation of lung epithelial cells. Cancer Res. 71:3087–97 [Google Scholar]
  117. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE. 117.  et al. 2007. A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat. Genet. 39:237–42 [Google Scholar]
  118. Azim HA Jr, Ganti AK. 118.  2006. Targeted therapy in advanced non–small cell lung cancer (NSCLC): Where do we stand?. Cancer Treat. Rev. 32:630–36 [Google Scholar]
  119. Dy GK, Adjei AA. 119.  2006. Angiogenesis inhibitors in lung cancer: a promise fulfilled. Clin. Lung Cancer 7:Suppl. 4145–49 [Google Scholar]
  120. Sandler A, Herbst R. 120.  2006. Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. Clin. Cancer Res. 12:S4421–25 [Google Scholar]
  121. Spicer J, Chowdhury S, Harper P. 121.  2007. Targeting novel and established therapies for non–small cell lung cancer. Cancer Lett. 250:9–16 [Google Scholar]
  122. Auberger J, Loeffler-Ragg J, Wurzer W, Hilbe W. 122.  2006. Targeted therapies in non–small cell lung cancer: proven concepts and unfulfilled promises. Curr. Cancer Drug Targets 6:271–94 [Google Scholar]
  123. Bunn PA Jr, Dziadziuszko R, Varella-Garcia M, Franklin WA, Witta SE. 123.  et al. 2006. Biological markers for non–small cell lung cancer patient selection for epidermal growth factor receptor tyrosine kinase inhibitor therapy. Clin. Cancer Res. 12:3652–56 [Google Scholar]
  124. Herman JG, Baylin SB. 124.  2003. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349:2042–54 [Google Scholar]
  125. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. 125.  1999. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21:103–7 [Google Scholar]
  126. Yang AS, Doshi KD, Choi SW, Mason JB, Mannari RK. 126.  et al. 2006. DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia. Cancer Res. 66:5495–503 [Google Scholar]
  127. Gore SD, Baylin S, Sugar E, Carraway H, Miller CB. 127.  et al. 2006. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 66:6361–69 [Google Scholar]
  128. Belinsky SA, Klinge DM, Stidley CA, Issa JP, Herman JG. 128.  2003. Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Res. 63:7089–93 [Google Scholar]
  129. March TH, Marron-Terada PG, Belinsky SA. 129.  2001. Refinement of an orthotopic lung cancer model in the nude rat. Vet. Pathol. 38:483–90 [Google Scholar]
  130. Belinsky SA, Grimes MJ, Picchi MA, Mitchell HD, Stidley CA. 130.  et al. 2011. Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. Cancer Res. 71:454–62 [Google Scholar]
  131. Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M. 131.  et al. 2011. Combination epigenetic therapy has efficacy in patients with refractory advanced non–small cell lung cancer. Cancer Discov. 1:598–607 [Google Scholar]
  132. Ho DH, Frei E. 132.  1971. Clinical pharmacology of 1-β-darabinofuranosyl cytosine. Clin. Pharmacol. Ther. 12:944–54 [Google Scholar]
  133. Fitzgerald SM, Royal RK, Osborne WR, Roy JD, Wilson JW, Ferrell RE. 133.  2006. Identification of functional single nucleotide polymorphism haplotypes in the cytidine deaminase promoter. Hum. Genet. 119:276–83 [Google Scholar]
  134. Mahfouz RZ, Jankowska A, Ebrahem Q, Gu X, Visconte V. 134.  et al. 2013. Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin. Cancer Res. 19:938–48 [Google Scholar]
  135. Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T. 135.  2011. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myeloid leukemia. J. Clin. Oncol. 29:2521–27 [Google Scholar]
  136. Reed MD, Tellez CS, Grimes MJ, Picchi MA, Tessema M. 136.  et al. 2013. Aerosolized 5-azacytidine suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. Br. J. Cancer 109:1775–81 [Google Scholar]
  137. Liu F, Barsyte-Lovejoy D, Allali-Hassani A, He Y, Herold JM. 137.  et al. 2011. Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines. J. Med. Chem. 54:6139–50 [Google Scholar]
  138. Dhanak D. 138.  2012. Inhibition of methyltransferase EZH2. Cancer Res. 72:SY02 (Abstr.) [Google Scholar]
  139. Champiat S, Ileana E, Giaccone G, Besse B, Mountzios G. 139.  et al. 2014. Incorporating immune-checkpoint inhibitors into systemic therapy of NSCLC. J. Thorac. Oncol. 9:144–53 [Google Scholar]
  140. Wrangle J, Wang W, Koch A, Easwaran H, Mohammad HP. 140.  2013. Alterations of immune response of non–small cell lung cancer with azacytidine. Oncotarget 4:2067–79 [Google Scholar]
  141. Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN. 141.  2013. Programmed death ligand-1 expression in non–small cell lung cancer. Lab Investig. 94:107–16 [Google Scholar]
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