Epigenetics in lung cancer: What do DNA-methyltransferases do?

  • Uli Fehrenbach Institute of Radiology, Department of Diagnostic and Interventional Radiology, Charité Campus Virchow-Klinikum, Berlin, Germany
  • Gian Kayser, MD Institute of Surgical Pathology Department of Pathology University Medical Center Freiburg Freiburg


Despite recent advances in molecular characterization and targeted therapy approaches, lung cancer still remains the number one killer among malignant diseases worldwide. After understanding the impact of genetic mutations on malignant transformation, epigenetic changes have been focused on in recent times. Several studies could elucidate the potential of epigenetic alterations to not only increase invasiveness of cancer cells in cell culture and animal models but also to contribute to autonomous cellular growth and thus malignant transformation itself. Thus, epigenetic changes are nowadays acknowledged as a hallmark in cancer. Several enzymes are involved in the epigenetic equilibrium of DNA methylation and demethylation, one family being DNA methyl transferases (DNMT). Here, we give a review of the impact of DNMTs on the biology of lung cancer and additionally present some of our results within this context. Further, we are also giving a perspective on future treatment options arising from the current literature and our results.


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1. WHO. World health statistics 2013. Geneva: World Health Organisation; 2013.
2. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. [Internet]. International Agency for Research on Cancer; 2013. 2012. Available from: http://globocan.iarc.fr.
3. Bray F RJ, Masuyer E, Ferlay J. Estimates of global cancer prevalence for 27 sites in the adult population in 2008. International journal of cancer Journal international du cancer. 2013;132(5):1133-45.
4. Wu C, Morris JR. Genes, genetics, and epigenetics: a correspondence. Science (New York, NY). 2001;293(5532):1103-5.
5. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Seminars in reproductive medicine. 2009;27(5):351-7.
6. Marmorstein R, Trievel RC. Histone modifying enzymes: structures, mechanisms, and specificities. Biochimica et biophysica acta. 2009;1789(1):58-68.
7. Antequera F, Bird A. Number of CpG islands and genes in human and mouse. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(24):11995-9.
8. Tang M, Xu W, Wang Q, Xiao W, Xu R. Potential of DNMT and its Epigenetic Regulation for Lung Cancer Therapy. Current genomics. 2009;10(5):336-52.
9. Clouaire T, Stancheva I. Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin? Cellular and molecular life sciences : CMLS. 2008;65(10):1509-22.
10. Jurkowski TP, Meusburger M, Phalke S, Helm M, Nellen W, Reuter G, et al. Human DNMT2 methylates tRNA(Asp) molecules using a DNA methyltransferase-like catalytic mechanism. RNA (New York, NY). 2008;14(8):1663-70.
11. Bai S, Ghoshal K, Datta J, Majumder S, Yoon SO, Jacob ST. DNA methyltransferase 3b regulates nerve growth factor-induced differentiation of PC12 cells by recruiting histone deacetylase 2. Molecular and cellular biology. 2005;25(2):751-66.
12. Jair KW, Bachman KE, Suzuki H, Ting AH, Rhee I, Yen RW, et al. De novo CpG island methylation in human cancer cells. Cancer research. 2006;66(2):682-92.
13. Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007;448(7154):714-7.
14. Feinberg AP, Koldobskiy MA, Gondor A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nature reviews Genetics. 2016;17(5):284-99.
15. Chen C, Yin N, Yin B, Lu Q. DNA methylation in thoracic neoplasms. Cancer letters. 2011;301(1):7-16.
16. Bird A. DNA methylation patterns and epigenetic memory. Genes & development. 2002;16(1):6-21.
17. Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nature genetics. 2000;24(2):132-8.
18. Maruyama R, Sugio K, Yoshino I, Maehara Y, Gazdar AF. Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinoma. Cancer. 2004;100(7):1472-7.
19. Jin B, Robertson KD. DNA methyltransferases, DNA damage repair, and cancer. Advances in experimental medicine and biology. 2013;754:3-29.
20. Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, Wang Z, et al. High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(1):252-7.
21. Pogribny IP, Beland FA. DNA hypomethylation in the origin and pathogenesis of human diseases. Cellular and molecular life sciences : CMLS. 2009;66(14):2249-61.
22. Watts GS, Futscher BW, Holtan N, Degeest K, Domann FE, Rose SL. DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage. BMC medical genomics. 2008;1:47.
23. Vera E, Canela A, Fraga MF, Esteller M, Blasco MA. Epigenetic regulation of telomeres in human cancer. Oncogene. 2008;27(54):6817-33.
24. Wong NC, Wong LH, Quach JM, Canham P, Craig JM, Song JZ, et al. Permissive transcriptional activity at the centromere through pockets of DNA hypomethylation. PLoS genetics. 2006;2(2):e17.
25. Howard G, Eiges R, Gaudet F, Jaenisch R, Eden A. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene. 2008;27(3):404-8.
26. Dammann R, Strunnikova M, Schagdarsurengin U, Rastetter M, Papritz M, Hattenhorst UE, et al. CpG island methylation and expression of tumour-associated genes in lung carcinoma. European journal of cancer (Oxford, England : 1990). 2005;41(8):1223-36.
27. Pastuszak-Lewandoska D, Kordiak J, Migdalska-Sek M, Czarnecka KH, Antczak A, Gorski P, et al. Quantitative analysis of mRNA expression levels and DNA methylation profiles of three neighboring genes: FUS1, NPRL2/G21 and RASSF1A in non-small cell lung cancer patients. Respiratory research. 2015;16:76.
28. Vallbohmer D, Brabender J, Yang D, Schneider PM, Metzger R, Danenberg KD, et al. DNA methyltransferases messenger RNA expression and aberrant methylation of CpG islands in non-small-cell lung cancer: association and prognostic value. Clinical lung cancer. 2006;8(1):39-44.
29. Kim H, Kwon YM, Kim JS, Han J, Shim YM, Park J, et al. Elevated mRNA levels of DNA methyltransferase-1 as an independent prognostic factor in primary nonsmall cell lung cancer. Cancer. 2006;107(5):1042-9.
30. Liu WB, Cui ZH, Ao L, Zhou ZY, Zhou YH, Yuan XY, et al. Aberrant methylation accounts for cell adhesion-related gene silencing during 3-methylcholanthrene and diethylnitrosamine induced multistep rat lung carcinogenesis associated with overexpression of DNA methyltransferases 1 and 3a. Toxicology and applied pharmacology. 2011;251(1):70-8.
31. Pandey M, Sultana S, Gupta KP. Involvement of epigenetics and microRNA-29b in the urethane induced inception and establishment of mouse lung tumors. Experimental and molecular pathology. 2014;96(1):61-70.
32. Lin RK, Hsu HS, Chang JW, Chen CY, Chen JT, Wang YC. Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer. Lung cancer. 2007;55(2):205-13.
33. Lin RK, Wu CY, Chang JW, Juan LJ, Hsu HS, Chen CY, et al. Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer research. 2010;70(14):5807-17.
34. Lin TS, Lee H, Chen RA, Ho ML, Lin CY, Chen YH, et al. An association of DNMT3b protein expression with P16INK4a promoter hypermethylation in non-smoking female lung cancer with human papillomavirus infection. Cancer letters. 2005;226(1):77-84.
35. Wang J, Walsh G, Liu DD, Lee JJ, Mao L. Expression of Delta DNMT3B variants and its association with promoter methylation of p16 and RASSF1A in primary non-small cell lung cancer. Cancer research. 2006;66(17):8361-6.
36. Wang L, Wang J, Sun S, Rodriguez M, Yue P, Jang SJ, et al. A novel DNMT3B subfamily, DeltaDNMT3B, is the predominant form of DNMT3B in non-small cell lung cancer. International journal of oncology. 2006;29(1):201-7.
37. Tang SC, Wu MF, Wong RH, Liu YF, Tang LC, Lai CH, et al. Epigenetic mechanisms for silencing glutathione S-transferase m2 expression by hypermethylated specificity protein 1 binding in lung cancer. Cancer. 2011;117(14):3209-21.
38. Suzuki M, Sunaga N, Shames DS, Toyooka S, Gazdar AF, Minna JD. RNA interference-mediated knockdown of DNA methyltransferase 1 leads to promoter demethylation and gene re-expression in human lung and breast cancer cells. Cancer research. 2004;64(9):3137-43.
39. Helm M. Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic acids research. 2006;34(2):721-33.
40. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(40):15805-10.
41. Wen S, Zhou W, Li CM, Hu J, Hu XM, Chen P, et al. Ki-67 as a prognostic marker in early-stage non-small cell lung cancer in Asian patients: a meta-analysis of published studies involving 32 studies. BMC cancer. 2015;15:520.
42. Eguchi K, Kanai Y, Kobayashi K, Hirohashi S. DNA hypermethylation at the D17S5 locus in non-small cell lung cancers: its association with smoking history. Cancer research. 1997;57(21):4913-5.
43. Belinsky SA, Nikula KJ, Baylin SB, Issa JP. Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(9):4045-50.
44. Brodie SA, Li G, El-Kommos A, Kang H, Ramalingam SS, Behera M, et al. Class I HDACs are mediators of smoke carcinogen-induced stabilization of DNMT1 and serve as promising targets for chemoprevention of lung cancer. Cancer prevention research (Philadelphia, Pa). 2014;7(3):351-61.
45. Vaissiere T, Sawan C, Herceg Z. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutation research. 2008;659(1-2):40-8.
46. Virmani AK, Tsou JA, Siegmund KD, Shen LY, Long TI, Laird PW, et al. Hierarchical clustering of lung cancer cell lines using DNA methylation markers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002;11(3):291-7.
47. Shinjo K, Okamoto Y, An B, Yokoyama T, Takeuchi I, Fujii M, et al. Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with distinct clinical characters of lung adenocarcinoma. Carcinogenesis. 2012;33(7):1277-85.
48. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(15):8681-6.
49. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nature reviews Genetics. 2006;7(1):21-33.
50. Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer. 2004;4(4):296-307.
51. Schmidt B, Liebenberg V, Dietrich D, Schlegel T, Kneip C, Seegebarth A, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer based on bronchial aspirates. BMC cancer. 2010;10:600.
52. Vendetti FP, Topper M, Huang P, Dobromilskaya I, Easwaran H, Wrangle J, et al. Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer. Oncotarget. 2014.
53. Tellez CS, Grimes MJ, Picchi MA, Liu Y, March TH, Reed MD, et al. SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome. International journal of cancer Journal international du cancer. 2014;135(9):2223-31.
54. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature genetics. 1999;21(1):103-7.
55. Mateen S, Raina K, Jain AK, Agarwal C, Chan D, Agarwal R. Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells. Epigenetics : official journal of the DNA Methylation Society. 2012;7(10):1161-72.
56. Mateen S, Raina K, Agarwal C, Chan D, Agarwal R. Silibinin synergizes with histone deacetylase and DNA methyltransferase inhibitors in upregulating E-cadherin expression together with inhibition of migration and invasion of human non-small cell lung cancer cells. The Journal of pharmacology and experimental therapeutics. 2013;345(2):206-14.
57. Belinsky SA, Grimes MJ, Picchi MA, Mitchell HD, Stidley CA, Tesfaigzi Y, et al. Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. Cancer research. 2011;71(2):454-62.
58. Kaminskyy VO, Surova OV, Vaculova A, Zhivotovsky B. Combined inhibition of DNA methyltransferase and histone deacetylase restores caspase-8 expression and sensitizes SCLC cells to TRAIL. Carcinogenesis. 2011;32(10):1450-8.
59. Fuller M, Klein M, Schmidt E, Rohde C, Gollner S, Schulze I, et al. 5-Azacytidine enhances efficacy of multiple chemotherapy drugs in AML and lung cancer with modulation of CpG methylation. International journal of oncology. 2014.
60. Momparler RL, Bouffard DY, Momparler LF, Dionne J, Belanger K, Ayoub J. Pilot phase I-II study on 5-aza-2'-deoxycytidine (Decitabine) in patients with metastatic lung cancer. Anti-cancer drugs. 1997;8(4):358-68.
61. Momparler RL, Ayoub J. Potential of 5-aza-2'-deoxycytidine (Decitabine) a potent inhibitor of DNA methylation for therapy of advanced non-small cell lung cancer. Lung cancer. 2001;34 Suppl 4:S111-5.
62. Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103(5):1635-40.
63. Aparicio A, Eads CA, Leong LA, Laird PW, Newman EM, Synold TW, et al. Phase I trial of continuous infusion 5-aza-2'-deoxycytidine. Cancer chemotherapy and pharmacology. 2003;51(3):231-9.
64. Belinsky SA, Klinge DM, Stidley CA, Issa JP, Herman JG, March TH, et al. Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer research. 2003;63(21):7089-93.
65. Candelaria M, Gallardo-Rincon D, Arce C, Cetina L, Aguilar-Ponce JL, Arrieta O, et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2007;18(9):1529-38.
66. Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer discovery. 2011;1(7):598-607.
67. Chen JC, Chiu MH, Nie RL, Cordell GA, Qiu SX. Cucurbitacins and cucurbitane glycosides: structures and biological activities. Natural product reports. 2005;22(3):386-99.
68. Shukla S, Khan S, Kumar S, Sinha S, Farhan M, Bora HK, et al. Cucurbitacin B Alters the Expression of Tumor-Related Genes by Epigenetic Modifications in NSCLC and Inhibits NNK-Induced Lung Tumorigenesis. Cancer prevention research (Philadelphia, Pa). 2015;8(6):552-62.
69. Kassis ES, Zhao M, Hong JA, Chen GA, Nguyen DM, Schrump DS. Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells. The Journal of thoracic and cardiovascular surgery. 2006;131(2):298-306.
70. Winquist E, Knox J, Ayoub JP, Wood L, Wainman N, Reid GK, et al. Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study. Investigational new drugs. 2006;24(2):159-67.
71. Lin RK, Hsu CH, Wang YC. Mithramycin A inhibits DNA methyltransferase and metastasis potential of lung cancer cells. Anti-cancer drugs. 2007;18(10):1157-64.
How to Cite
FEHRENBACH, Uli; KAYSER, MD, Gian. Epigenetics in lung cancer: What do DNA-methyltransferases do?. Diagnostic Pathology, [S.l.], v. 3, n. 1, aug. 2017. ISSN 2364-4893. Available at: <http://www.diagnosticpathology.eu/content/index.php/dpath/article/view/250>. Date accessed: 05 feb. 2023. doi: https://doi.org/10.17629/www.diagnosticpathology.eu-2017-3:250.
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