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Current Cancer Drug Targets

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Research Article

MGMT Epigenetics: The Influence of Gene Body Methylation and Other Insights Derived from Integrated Methylomic, Transcriptomic, and Chromatin Analyses in Various Cancer Types

Author(s): Manny D. Bacolod* and Francis Barany

Volume 21, Issue 4, 2021

Published on: 02 February, 2021

Page: [360 - 374] Pages: 15

DOI: 10.2174/1568009621666210203111620

Price: $65

Abstract

Background: MGMT (O6-methylguanine-DNA methyltransferase) is primarily responsible for limiting the activity of some widely used chemotherapeutic agents, including temozolomide (TMZ) and carmustine (BCNU). The gene encoding this protein is epigenetically regulated, and assessment of methylation at its promoter region is used to predict glioma patients’ response to TMZ.

Methods: In this report, we employed a bioinformatic approach to elucidate MGMT’s epigenetic regulation. Integrated for the analysis were genome-wide methylation and transcription datasets for > 8,600 human tissue (representing 31 distinct cancer types) and 500 human cancer cell line samples. Also crucial to the interpretation of results were publicly available data from the ENCODE Project: tracks for histone modifications (via ChIP-seq) and DNase I hypersensitivity (via DNaseseq), as well as methylation and transcription data for representative cell lines (HeLa-S3, HMEC, K562).

Results and Discussion: We were able to validate (perhaps more comprehensively) the contrasting influences of CpG methylation at promoter region and at gene body on MGMT transcription. While the MGMT promoter is populated by CpG sites whose methylation levels displayed high negative correlation (R) with MGMT mRNA counts, the gene body harbors CpG sites exhibiting high positive R values. The promoter CpG sites with very high negative R’s across cancer types include cg12981137, cg12434587, and cg00618725. Among the notable gene body CpG sites (high positive R’s across cancer types) are cg00198994 (Intron 1), cg04473030 (Intron 2), and cg07367735 (Intron 4). For certain cancer types, such as melanoma, gene body methylation appears to be a better predictor of MGMT transcription (compared to promoter methylation). In general, the CpG methylation v. MGMT expression R values are higher in cell lines relative to tissues. Also, these correlations are noticeably more prominent in certain cancer types such as colorectal, adrenocortical, esophageal, skin, and head and neck cancers, as well as glioblastoma. As expected, hypomethylation at the promoter region is associated with more open chromatin, and enrichment of histone marks H3K4m1, H3K4m2, H3K4m3, and H3K9ac.

Conclusion: Overall, our analysis illustrated the contrasting influence of promoter and gene body methylation on MGMT expression. These observations may help improve diagnostic assays for MGMT.

Keywords: MGMT, epigenetics, methylation, TCGA, ENCODE, cancer.

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[1]
Pegg, A.E. Properties of mammalian O6-alkylguanine-DNA transferases. Mutat. Res., 1990, 233(1-2), 165-175.
[http://dx.doi.org/10.1016/0027-5107(90)90160-6] [PMID: 2233798]
[2]
Fahrer, J.; Kaina, B. O6-methylguanine-DNA methyltransferase in the defense against N-nitroso compounds and colorectal cancer. Carcinogenesis, 2013, 34(11), 2435-2442.
[http://dx.doi.org/10.1093/carcin/bgt275] [PMID: 23929436]
[3]
Kaina, B.; Christmann, M.; Naumann, S.; Roos, W.P. MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst.), 2007, 6(8), 1079-1099.
[http://dx.doi.org/10.1016/j.dnarep.2007.03.008] [PMID: 17485253]
[4]
Dolan, M.E.; Pegg, A.E. O6-benzylguanine and its role in chemotherapy. Clin. Cancer Res., 1997, 3(6), 837-847.
[PMID: 9815757]
[5]
Venur, V.A.; Peereboom, D.M.; Ahluwalia, M.S. Current medical treatment of glioblastoma. Cancer Treat. Res., 2015, 163, 103-115.
[http://dx.doi.org/10.1007/978-3-319-12048-5_7] [PMID: 25468228]
[6]
Kuruvilla, J. Standard therapy of advanced Hodgkin lymphoma. Hematology (Am. Soc. Hematol. Educ. Program), 2009, 497-506.
[http://dx.doi.org/10.1182/asheducation-2009.1.497] [PMID: 20008235]
[7]
Harries, M.; Malvehy, J.; Lebbe, C.; Heron, L.; Amelio, J.; Szabo, Z.; Schadendorf, D. Treatment patterns of advanced malignant melanoma (stage III-IV) - A review of current standards in Europe. Eur. J. Cancer, 2016, 60, 179-189.
[http://dx.doi.org/10.1016/j.ejca.2016.01.011] [PMID: 27118416]
[8]
Bacolod, M.D.; Johnson, S.P.; Ali-Osman, F.; Modrich, P.; Bullock, N.S.; Colvin, O.M.; Bigner, D.D.; Friedman, H.S. Mechanisms of resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea in human medulloblastoma and rhabdomyosarcoma. Mol. Cancer Ther., 2002, 1(9), 727-736.
[PMID: 12479369]
[9]
Bacolod, M.D.; Johnson, S.P.; Pegg, A.E.; Dolan, M.E.; Moschel, R.C.; Bullock, N.S.; Fang, Q.; Colvin, O.M.; Modrich, P.; Bigner, D.D.; Friedman, H.S. Brain tumor cell lines resistant to O6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O6-alkylguanine-DNA alkyltransferase mutations. Mol. Cancer Ther., 2004, 3(9), 1127-1135.
[PMID: 15367707]
[10]
von Bueren, A.O.; Bacolod, M.D.; Hagel, C.; Heinimann, K.; Fedier, A.; Kordes, U.; Pietsch, T.; Koster, J.; Grotzer, M.A.; Friedman, H.S.; Marra, G.; Kool, M.; Rutkowski, S. Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours. Br. J. Cancer, 2012, 107(8), 1399-1408.
[http://dx.doi.org/10.1038/bjc.2012.403] [PMID: 22976800]
[11]
Mansouri, A.; Hachem, L.D.; Mansouri, S.; Nassiri, F.; Laperriere, N.J.; Xia, D.; Lindeman, N.I.; Wen, P.Y.; Chakravarti, A.; Mehta, M.P.; Hegi, M.E.; Stupp, R.; Aldape, K.D.; Zadeh, G. MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges. Neuro-oncol., 2019, 21(2), 167-178.
[http://dx.doi.org/10.1093/neuonc/noy132] [PMID: 30189035]
[12]
Cankovic, M.; Nikiforova, M.N.; Snuderl, M.; Adesina, A.M.; Lindeman, N.; Wen, P.Y.; Lee, E.Q. The role of MGMT testing in clinical practice: a report of the association for molecular pathology. J. Mol. Diagn., 2013, 15(5), 539-555.
[http://dx.doi.org/10.1016/j.jmoldx.2013.05.011] [PMID: 23871769]
[13]
Cabrini, G.; Fabbri, E.; Lo Nigro, C.; Dechecchi, M.C.; Gambari, R. Regulation of expression of O6-methylguanine-DNA methyltransferase and the treatment of glioblastoma (Review). Int. J. Oncol., 2015, 47(2), 417-428.
[http://dx.doi.org/10.3892/ijo.2015.3026] [PMID: 26035292]
[14]
Christmann, M.; Kaina, B. Epigenetic regulation of DNA repair genes and implications for tumor therapy. Mutat. Res., 2019, 780, 15-28.
[http://dx.doi.org/10.1016/j.mrrev.2017.10.001] [PMID: 31395346]
[15]
Costello, J.F.; Futscher, B.W.; Tano, K.; Graunke, D.M.; Pieper, R.O. Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. J. Biol. Chem., 1994, 269(25), 17228-17237.
[PMID: 8006031]
[16]
Harris, L.C.; Remack, J.S.; Brent, T.P. In vitro methylation of the human O6-methylguanine-DNA methyltransferase promoter reduces transcription. Biochim. Biophys. Acta, 1994, 1217(2), 141-146.
[http://dx.doi.org/10.1016/0167-4781(94)90027-2] [PMID: 8110828]
[17]
Zhang, J.; Yang, J.H.; Quan, J.; Kang, X.; Wang, H.J.; Dai, P.G. Identification of MGMT promoter methylation sites correlating with gene expression and IDH1 mutation in gliomas. Tumour Biol., 2016, 37(10), 13571-13579.
[http://dx.doi.org/10.1007/s13277-016-5153-4] [PMID: 27468718]
[18]
Bhat, A.A.; Wani, H.A.; Waza, A.A.; Malik, R.A.; Masood, A.; Jeelani, S.; Kadla, S.; Majid, S. Diminished expression of MGMT & RASSF1A genes in gastric cancer in ethnic population of Kashmir. J. Gastrointest. Oncol., 2016, 7(6), 989-995.
[http://dx.doi.org/10.21037/jgo.2016.06.07] [PMID: 28078123]
[19]
Asiaf, A.; Ahmad, S.T.; Malik, A.A.; Aziz, S.A.; Rasool, Z.; Masood, A.; Zargar, M.A. Protein expression and methylation of MGMT, a DNA repair gene and their correlation with clinicopathological parameters in invasive ductal carcinoma of the breast. Tumour Biol., 2015, 36(8), 6485-6496.
[http://dx.doi.org/10.1007/s13277-015-3339-9] [PMID: 25820821]
[20]
Toffolatti, L.; Scquizzato, E.; Cavallin, S.; Canal, F.; Scarpa, M.; Stefani, P.M.; Gherlinzoni, F.; Dei Tos, A.P. MGMT promoter methylation and correlation with protein expression in primary central nervous system lymphoma. Virchows Arch., 2014, 465(5), 579-586.
[http://dx.doi.org/10.1007/s00428-014-1622-6] [PMID: 25031012]
[21]
Ishiguro, K.; Shyam, K.; Penketh, P.G.; Baumann, R.P.; Sartorelli, A.C.; Rutherford, T.J.; Ratner, E.S. Expression of O6-Methylguanine-DNA Methyltransferase Examined by Alkyl-transfer assays, methylation-specific PCR and western blots in tumors and matched normal tissue. J. Cancer Ther., 2013, 4(4), 919-931.
[http://dx.doi.org/10.4236/jct.2013.44103] [PMID: 23946891]
[22]
Tang, K.; Jin, Q.; Yan, W.; Zhang, W.; You, G.; Liu, Y.; Jiang, T. Clinical correlation of MGMT protein expression and promoter methylation in Chinese glioblastoma patients. Med. Oncol., 2012, 29(2), 1292-1296.
[http://dx.doi.org/10.1007/s12032-011-9901-4] [PMID: 21394635]
[23]
Kishida, Y.; Natsume, A.; Toda, H.; Toi, Y.; Motomura, K.; Koyama, H.; Matsuda, K.; Nakayama, O.; Sato, M.; Suzuki, M.; Kondo, Y.; Wakabayashi, T. Correlation between quantified promoter methylation and enzymatic activity of O6-methylguanine-DNA methyltransferase in glioblastomas. Tumour Biol., 2012, 33(2), 373-381.
[http://dx.doi.org/10.1007/s13277-012-0319-1] [PMID: 22274924]
[24]
Uno, M.; Oba-Shinjo, S.M.; Camargo, A.A.; Moura, R.P.; Aguiar, P.H.; Cabrera, H.N.; Begnami, M.; Rosemberg, S.; Teixeira, M.J.; Marie, S.K. Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma. Clinics (São Paulo), 2011, 66(10), 1747-1755.
[http://dx.doi.org/10.1590/S1807-59322011001000013] [PMID: 22012047]
[25]
Malley, D.S.; Hamoudi, R.A.; Kocialkowski, S.; Pearson, D.M.; Collins, V.P.; Ichimura, K. A distinct region of the MGMT CpG island critical for transcriptional regulation is preferentially methylated in glioblastoma cells and xenografts. Acta Neuropathol., 2011, 121(5), 651-661.
[http://dx.doi.org/10.1007/s00401-011-0803-5] [PMID: 21287394]
[26]
Shah, N.; Lin, B.; Sibenaller, Z.; Ryken, T.; Lee, H.; Yoon, J.G.; Rostad, S.; Foltz, G. Comprehensive analysis of MGMT promoter methylation: correlation with MGMT expression and clinical response in GBM. PLoS One, 2011, 6(1)
[http://dx.doi.org/10.1371/journal.pone.0016146] [PMID: 21249131]
[27]
Jha, P.; Suri, V.; Jain, A.; Sharma, M.C.; Pathak, P.; Jha, P.; Srivastava, A.; Suri, A.; Gupta, D.; Chosdol, K.; Chattopadhyay, P.; Sarkar, C. O6-methylguanine DNA methyltransferase gene promoter methylation status in gliomas and its correlation with other molecular alterations: first Indian report with review of challenges for use in customized treatment. Neurosurgery, 2010, 67(6), 1681-1691.
[http://dx.doi.org/10.1227/NEU.0b013e3181f743f5] [PMID: 21107199]
[28]
Esteller, M.; Hamilton, S.R.; Burger, P.C.; Baylin, S.B.; Herman, J.G. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res., 1999, 59(4), 793-797.
[PMID: 10029064]
[29]
Qian, X.C.; Brent, T.P. Methylation hot spots in the 5′ flanking region denote silencing of the O6-methylguanine-DNA methyltransferase gene. Cancer Res., 1997, 57(17), 3672-3677.
[PMID: 9288770]
[30]
Qian, X.; von Wronski, M.A.; Brent, T.P. Localization of methylation sites in the human O6-methylguanine-DNA methyltransferase promoter: correlation with gene suppression. Carcinogenesis, 1995, 16(6), 1385-1390.
[http://dx.doi.org/10.1093/carcin/16.6.1385] [PMID: 7788859]
[31]
Christmann, M.; Pick, M.; Lage, H.; Schadendorf, D.; Kaina, B. Acquired resistance of melanoma cells to the antineoplastic agent fotemustine is caused by reactivation of the DNA repair gene MGMT. Int. J. Cancer, 2001, 92(1), 123-129.
[http://dx.doi.org/10.1002/1097-0215(200102)9999:9999<::AID-IJC1160>3.0.CO;2-V] [PMID: 11279615]
[32]
Wang, Y.; Kato, T.; Ayaki, H.; Ishizaki, K.; Tano, K.; Mitra, S.; Ikenaga, M. Correlation between DNA methylation and expression of O6-methylguanine-DNA methyltransferase gene in cultured human tumor cells. Mutat. Res., 1992, 273(2), 221-230.
[http://dx.doi.org/10.1016/0921-8777(92)90083-F] [PMID: 1372105]
[33]
Bearzatto, A.; Szadkowski, M.; Macpherson, P.; Jiricny, J.; Karran, P. Epigenetic regulation of the MGMT and hMSH6 DNA repair genes in cells resistant to methylating agents. Cancer Res., 2000, 60(12), 3262-3270.
[PMID: 10866320]
[34]
Moen, E.L.; Stark, A.L.; Zhang, W.; Dolan, M.E.; Godley, L.A. The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide. Mol. Cancer Ther., 2014, 13(5), 1334-1344.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0924] [PMID: 24568970]
[35]
Nakagawachi, T.; Soejima, H.; Urano, T.; Zhao, W.; Higashimoto, K.; Satoh, Y.; Matsukura, S.; Kudo, S.; Kitajima, Y.; Harada, H.; Furukawa, K.; Matsuzaki, H.; Emi, M.; Nakabeppu, Y.; Miyazaki, K.; Sekiguchi, M.; Mukai, T. Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer. Oncogene, 2003, 22(55), 8835-8844.
[http://dx.doi.org/10.1038/sj.onc.1207183] [PMID: 14647440]
[36]
Danam, R.P.; Howell, S.R.; Brent, T.P.; Harris, L.C. Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins. Mol. Cancer Ther., 2005, 4(1), 61-69.
[PMID: 15657354]
[37]
Zhao, W.; Soejima, H.; Higashimoto, K.; Nakagawachi, T.; Urano, T.; Kudo, S.; Matsukura, S.; Matsuo, S.; Joh, K.; Mukai, T. The essential role of histone H3 Lys9 di-methylation and MeCP2 binding in MGMT silencing with poor DNA methylation of the promoter CpG island. J. Biochem., 2005, 137(3), 431-440.
[http://dx.doi.org/10.1093/jb/mvi048] [PMID: 15809347]
[38]
Meng, C.F.; Zhu, X.J.; Peng, G.; Dai, D.Q. Role of histone modifications and DNA methylation in the regulation of O6-methylguanine-DNA methyltransferase gene expression in human stomach cancer cells. Cancer Invest., 2010, 28(4), 331-339.
[http://dx.doi.org/10.1080/07357900903179633] [PMID: 19857042]
[39]
Kitange, G.J.; Mladek, A.C.; Carlson, B.L.; Schroeder, M.A.; Pokorny, J.L.; Cen, L.; Decker, P.A.; Wu, W.; Lomberk, G.A.; Gupta, S.K.; Urrutia, R.A.; Sarkaria, J.N. Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts. Clin. Cancer Res., 2012, 18(15), 4070-4079.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-0560] [PMID: 22675172]
[40]
Choi, E.J.; Cho, B.J.; Lee, D.J.; Hwang, Y.H.; Chun, S.H.; Kim, H.H.; Kim, I.A. Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases. BMC Cancer, 2014, 14, 17.
[http://dx.doi.org/10.1186/1471-2407-14-17] [PMID: 24418474]
[41]
ENCODE_Project_Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science, 2004, 306, 636-640.
[http://dx.doi.org/10.1126/science.1105136]
[42]
Kaiser, J. National Institutes of Health. NCI gears up for cancer genome project. Science, 2005, 307(5713), 1182.
[http://dx.doi.org/10.1126/science.307.5713.1182a] [PMID: 15731412]
[43]
Zhu, J.; Sanborn, J.Z.; Benz, S.; Szeto, C.; Hsu, F.; Kuhn, R.M.; Karolchik, D.; Archie, J.; Lenburg, M.E.; Esserman, L.J.; Kent, W.J.; Haussler, D.; Wang, T. The UCSC cancer genomics browser. Nat. Methods, 2009, 6(4), 239-240.
[http://dx.doi.org/10.1038/nmeth0409-239] [PMID: 19333237]
[44]
Goldman, M.; Craft, B.; Swatloski, T.; Ellrott, K.; Cline, M.; Diekhans, M.; Ma, S.; Wilks, C.; Stuart, J.; Haussler, D.; Zhu, J. The UCSC cancer genomics browser: update 2013. Nucleic Acids Res., 2013, 41(Database issue), D949-D954.
[http://dx.doi.org/10.1093/nar/gks1008] [PMID: 23109555]
[45]
Iorio, F.; Knijnenburg, T.A.; Vis, D.J.; Bignell, G.R.; Menden, M.P.; Schubert, M.; Aben, N.; Gonçalves, E.; Barthorpe, S.; Lightfoot, H.; Cokelaer, T.; Greninger, P.; van Dyk, E.; Chang, H.; de Silva, H.; Heyn, H.; Deng, X.; Egan, R.K.; Liu, Q.; Mironenko, T.; Mitropoulos, X.; Richardson, L.; Wang, J.; Zhang, T.; Moran, S.; Sayols, S.; Soleimani, M.; Tamborero, D.; Lopez-Bigas, N.; Ross-Macdonald, P.; Esteller, M.; Gray, N.S.; Haber, D.A.; Stratton, M.R.; Benes, C.H.; Wessels, L.F.A.; Saez-Rodriguez, J.; McDermott, U.; Garnett, M.J. A landscape of pharmacogenomic interactions in cancer. Cell, 2016, 166(3), 740-754.
[http://dx.doi.org/10.1016/j.cell.2016.06.017] [PMID: 27397505]
[46]
Bacolod, M.D.; Das, S.K.; Sokhi, U.K.; Bradley, S.; Fenstermacher, D.A.; Pellecchia, M.; Emdad, L.; Sarkar, D.; Fisher, P.B. Examination of epigenetic and other molecular factors associated with mda-9/syntenin dysregulation in cancer through integrated analyses of public genomic datasets. Adv. Cancer Res., 2015, 127, 49-121.
[http://dx.doi.org/10.1016/bs.acr.2015.04.006] [PMID: 26093898]
[47]
Bernstein, B.E.; Kamal, M.; Lindblad-Toh, K.; Bekiranov, S.; Bailey, D.K.; Huebert, D.J.; McMahon, S.; Karlsson, E.K.; Kulbokas, E.J., III; Gingeras, T.R.; Schreiber, S.L.; Lander, E.S. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell, 2005, 120(2), 169-181.
[http://dx.doi.org/10.1016/j.cell.2005.01.001] [PMID: 15680324]
[48]
Boyle, A.P.; Davis, S.; Shulha, H.P.; Meltzer, P.; Margulies, E.H.; Weng, Z.; Furey, T.S.; Crawford, G.E. High-resolution mapping and characterization of open chromatin across the genome. Cell, 2008, 132(2), 311-322.
[http://dx.doi.org/10.1016/j.cell.2007.12.014] [PMID: 18243105]
[49]
Sandoval, J.; Heyn, H.; Moran, S.; Serra-Musach, J.; Pujana, M.A.; Bibikova, M.; Esteller, M. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics, 2011, 6(6), 692-702.
[http://dx.doi.org/10.4161/epi.6.6.16196] [PMID: 21593595]
[50]
Fishilevich, S; Nudel, R; Rappaport, N; Hadar, R; Plaschkes, I; Iny Stein, T; Rosen, N; Kohn, A; Twik, M; Safran, M; Lancet, D; Cohen, D. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford), 2017.
[http://dx.doi.org/10.1093/database/bax028]
[51]
Gay, L.; Baker, A.M.; Graham, T.A. Tumour Cell Heterogeneity. F1000 Res., 2016, 5, 5.
[http://dx.doi.org/10.12688/f1000research.7210.1] [PMID: 26973786]
[52]
Bacolod, M.D.; Barany, F.; Pilones, K.; Fisher, P.B.; de Castro, R.J. Pathways- and epigenetic-based assessment of relative immune infiltration in various types of solid tumors. Adv. Cancer Res., 2018, •••, 142.
[PMID: 30885360]
[53]
Ghirlando, R.; Giles, K.; Gowher, H.; Xiao, T.; Xu, Z.; Yao, H.; Felsenfeld, G. Chromatin domains, insulators, and the regulation of gene expression. Biochim. Biophys. Acta, 2012, 1819(7), 644-651.
[http://dx.doi.org/10.1016/j.bbagrm.2012.01.016] [PMID: 22326678]
[54]
Ernst, J.; Kheradpour, P.; Mikkelsen, T.S.; Shoresh, N.; Ward, L.D.; Epstein, C.B.; Zhang, X.; Wang, L.; Issner, R.; Coyne, M.; Ku, M.; Durham, T.; Kellis, M.; Bernstein, B.E. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature, 2011, 473(7345), 43-49.
[http://dx.doi.org/10.1038/nature09906] [PMID: 21441907]
[55]
Campbell, M.J.; Turner, B.M. Altered histone modifications in cancer. Adv. Exp. Med. Biol., 2013, 754, 81-107.
[http://dx.doi.org/10.1007/978-1-4419-9967-2_4] [PMID: 22956497]
[56]
Kondo, Y.; Shen, L.; Issa, J.P. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol. Cell. Biol., 2003, 23(1), 206-215.
[http://dx.doi.org/10.1128/MCB.23.1.206-215.2003] [PMID: 12482974]
[57]
Watts, G.S.; Pieper, R.O.; Costello, J.F.; Peng, Y.M.; Dalton, W.S.; Futscher, B.W. Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene. Mol. Cell. Biol., 1997, 17(9), 5612-5619.
[http://dx.doi.org/10.1128/MCB.17.9.5612] [PMID: 9271436]
[58]
Yang, X.; Han, H.; De Carvalho, D.D.; Lay, F.D.; Jones, P.A.; Liang, G. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell, 2014, 26(4), 577-590.
[http://dx.doi.org/10.1016/j.ccr.2014.07.028] [PMID: 25263941]
[59]
Gonçalves, C.S.; Xavier-Magalhães, A.; Martins, E.P.; Pinto, A.A.; Pires, M.M.; Pinheiro, C.; Reis, R.M.; Sousa, N.; Costa, B.M. A novel molecular link between HOXA9 and WNT6 in glioblastoma identifies a subgroup of patients with particular poor prognosis. Mol. Oncol., 2020, 14(6), 1224-1241.
[http://dx.doi.org/10.1002/1878-0261.12633] [PMID: 31923345]
[60]
Holderried, T.A.W.; de Vos, L.; Bawden, E.G.; Vogt, T.J.; Dietrich, J.; Zarbl, R.; Bootz, F.; Kristiansen, G.; Brossart, P.; Landsberg, J.; Dietrich, D. Molecular and immune correlates of TIM-3 (HAVCR2) and galectin 9 (LGALS9) mRNA expression and DNA methylation in melanoma. Clin. Epigenetics, 2019, 11(1), 161.
[http://dx.doi.org/10.1186/s13148-019-0752-8] [PMID: 31747929]
[61]
Wang, Y.; Zhu, W.; Chen, X.; Wei, G.; Jiang, G.; Zhang, G. Selenium-binding protein 1 transcriptionally activates p21 expression via p53-independent mechanism and its frequent reduction associates with poor prognosis in bladder cancer. J. Transl. Med., 2020, 18(1), 17.
[http://dx.doi.org/10.1186/s12967-020-02211-4] [PMID: 31918717]
[62]
Rondelet, G.; Wouters, J. Human DNA (cytosine-5)-methyltransferases: a functional and structural perspective for epigenetic cancer therapy. Biochimie, 2017, 139, 137-147.
[http://dx.doi.org/10.1016/j.biochi.2017.06.003] [PMID: 28600135]
[63]
Costello, J.F.; Futscher, B.W.; Kroes, R.A.; Pieper, R.O. Methylation-related chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6-methylguanine DNA methyltransferase gene in human glioma cell lines. Mol. Cell. Biol., 1994, 14(10), 6515-6521.
[http://dx.doi.org/10.1128/MCB.14.10.6515] [PMID: 7523853]
[64]
Lavon, I.; Fuchs, D.; Zrihan, D.; Efroni, G.; Zelikovitch, B.; Fellig, Y.; Siegal, T. Novel mechanism whereby nuclear factor kappaB mediates DNA damage repair through regulation of O(6)-methylguanine-DNA-methyltransferase. Cancer Res., 2007, 67(18), 8952-8959.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3820] [PMID: 17875738]
[65]
Bhakat, K.K.; Mitra, S. Regulation of the human O(6)-methylguanine-DNA methyltransferase gene by transcriptional coactivators cAMP response element-binding protein-binding protein and p300. J. Biol. Chem., 2000, 275(44), 34197-34204.
[http://dx.doi.org/10.1074/jbc.M005447200] [PMID: 10942771]
[66]
Boldogh, I.; Ramana, C.V.; Chen, Z.; Biswas, T.; Hazra, T.K.; Grösch, S.; Grombacher, T.; Mitra, S.; Kaina, B. Regulation of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling. Cancer Res., 1998, 58(17), 3950-3956.
[PMID: 9731508]
[67]
Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; Hau, P.; Brandes, A.A.; Gijtenbeek, J.; Marosi, C.; Vecht, C.J.; Mokhtari, K.; Wesseling, P.; Villa, S.; Eisenhauer, E.; Gorlia, T.; Weller, M.; Lacombe, D.; Cairncross, J.G.; Mirimanoff, R.O. European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol., 2009, 10(5), 459-466.
[http://dx.doi.org/10.1016/S1470-2045(09)70025-7] [PMID: 19269895]
[68]
Amatu, A.; Sartore-Bianchi, A.; Moutinho, C.; Belotti, A.; Bencardino, K.; Chirico, G.; Cassingena, A.; Rusconi, F.; Esposito, A.; Nichelatti, M.; Esteller, M.; Siena, S. Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer. Clin. Cancer Res., 2013, 19(8), 2265-2272.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3518] [PMID: 23422094]
[69]
Schraml, P.; von Teichman, A.; Mihic-Probst, D.; Simcock, M.; Ochsenbein, A.; Dummer, R.; Michielin, O.; Seifert, B.; Schläppi, M.; Moch, H.; von Moos, R. Predictive value of the MGMT promoter methylation status in metastatic melanoma patients receiving first-line temozolomide plus bevacizumab in the trial SAKK 50/07. Oncol. Rep., 2012, 28(2), 654-658.
[http://dx.doi.org/10.3892/or.2012.1826] [PMID: 22614944]
[70]
Gallitto, M.; Cheng He, R.; Inocencio, J.F.; Wang, H.; Zhang, Y.; Deikus, G.; Wasserman, I.; Strahl, M.; Smith, M.; Sebra, R.; Yong, R.L. Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1. J. Neurooncol., 2020, 147(3), 557-566.
[http://dx.doi.org/10.1007/s11060-020-03461-4] [PMID: 32193690]
[71]
Marchesi, F.; Turriziani, M.; Tortorelli, G.; Avvisati, G.; Torino, F.; De Vecchis, L. Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol. Res., 2007, 56(4), 275-287.
[http://dx.doi.org/10.1016/j.phrs.2007.08.003] [PMID: 17897837]
[72]
Tawbi, H.A.; Beumer, J.H.; Tarhini, A.A.; Moschos, S.; Buch, S.C.; Egorin, M.J.; Lin, Y.; Christner, S.; Kirkwood, J.M. Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis. Ann. Oncol., 2013, 24(4), 1112-1119.
[http://dx.doi.org/10.1093/annonc/mds591] [PMID: 23172636]
[73]
Dagogo-Jack, I.; Shaw, A.T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol., 2018, 15(2), 81-94.
[http://dx.doi.org/10.1038/nrclinonc.2017.166] [PMID: 29115304]
[74]
Verhaak, R.G.; Hoadley, K.A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M.D.; Miller, C.R.; Ding, L.; Golub, T.; Mesirov, J.P.; Alexe, G.; Lawrence, M.; O’Kelly, M.; Tamayo, P.; Weir, B.A.; Gabriel, S.; Winckler, W.; Gupta, S.; Jakkula, L.; Feiler, H.S.; Hodgson, J.G.; James, C.D.; Sarkaria, J.N.; Brennan, C.; Kahn, A.; Spellman, P.T.; Wilson, R.K.; Speed, T.P.; Gray, J.W.; Meyerson, M.; Getz, G.; Perou, C.M.; Hayes, D.N. Cancer Genome Atlas Research Network. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 2010, 17(1), 98-110.
[http://dx.doi.org/10.1016/j.ccr.2009.12.020] [PMID: 20129251]
[75]
Noushmehr, H.; Weisenberger, D.J.; Diefes, K.; Phillips, H.S.; Pujara, K.; Berman, B.P.; Pan, F.; Pelloski, C.E.; Sulman, E.P.; Bhat, K.P.; Verhaak, R.G.; Hoadley, K.A.; Hayes, D.N.; Perou, C.M.; Schmidt, H.K.; Ding, L.; Wilson, R.K.; Van Den Berg, D.; Shen, H.; Bengtsson, H.; Neuvial, P.; Cope, L.M.; Buckley, J.; Herman, J.G.; Baylin, S.B.; Laird, P.W.; Aldape, K. Cancer Genome Atlas Research Network. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell, 2010, 17(5), 510-522.
[http://dx.doi.org/10.1016/j.ccr.2010.03.017] [PMID: 20399149]

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