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DNA methylation and cancer: transcriptional regulation, prognostic, and therapeutic perspective

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Medical Oncology Aims and scope Submit manuscript

Abstract

DNA methylation is one among the major grounds of cancer progression which is characterized by the addition of a methyl group to the promoter region of the gene thereby causing gene silencing or increasing the probability of mutations; however, in bacteria, methylation is used as a defense mechanism where DNA protection is by addition of methyl groups making restriction enzymes unable to cleave. Hypermethylation and hypomethylation both pose as leading causes of oncogenesis; the former being more frequent which occurs at the CpG islands present in the promoter region of the genes, whereas the latter occurs globally in various genomic sequences. Reviewing methylation profiles would help in the detection and treatment of cancers. Demethylation is defined as preventing methyl group addition to the cytosine DNA base which could cause cancers in case of global hypomethylation, however, upon further investigation; it could be used as a therapeutic tool as well as for drug design in cancer treatment. In this review, we have studied the molecules that induce and enzymes (DNMTs) that bring about methylation as well as comprehend the correlation between methylation with transcription factors and various signaling pathways. DNA methylation has also been reviewed in terms of how it could serve as a prognostic marker and the various therapeutic drugs that have come into the market for reversing methylation opening an avenue toward curing cancers.

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Data availability

Data are available on request from the authors.

Abbreviations

CpG:

5′-Cytosine-phosphate-guanine-3′

mCpG:

Methyl CpG

DNMT:

DNA methyltransferase

TET:

Ten-eleven translocations

TSG:

Tumor suppressor gene

TSS:

Transcription start site

RB 1:

Retinoblastoma transcriptional corepressor 1

P53:

Protein 53

CDKN2A:

Cyclin-dependent kinase inhibitor 2A

CDKN2B:

Cyclin-dependent kinase inhibitor 2B

H-RAS:

Harvey rat sarcoma virus

c-Myc:

Cellular myelocytomatosis

NOTCH 1:

Neurogenic locus notch homolog protein 1

plau:

Plasminogen activator urokinase

AML:

Acute myeloid leukemia

TDG:

Thymine DNA glycosylase

TGB1:

Transforming growth factor beta 1

ETS:

Erythroblast transformation specific

MGMT:

O(6)-methylguanine DNA methyltransferase

EGFP:

Enhanced green fluorescent protein

MAPK:

Mitogen-activated protein kinase

CDH:

Cadherin

RASSF2A:

Ras association domain family 2

PTEN:

Phosphatase and Tensin Homolog deleted on Chromosome 10

E2F2:

E2F transcription factor

TF:

Transcription factor

NF–kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

REST:

RE1-Silencing Transcription factor

CTSC:

Cathepsin c

OCT 4:

Octamer-binding transcription factor 4

MBD:

Methyl-binding domain proteins

JAG 2:

Jagged canonical Notch ligand 2

ARF:

Alternative reading frame

MDM2:

Murine double minute 2

NRF2:

Nuclear factor erythroid 2-related factor 2

KEAP1:

Kelch-like ECH-associated protein 1

PIK3K:

Phosphoinositide 3-kinase

WNT:

Wingless-related integration site

TBX 2:

T-box transcription factor 2

TWIST1:

TWIST-related protein 1

AKT:

Ak strain transforming

ARE:

Antioxidant response element

SMAD:

Suppressor of Mothers against Decapentaplegic

PLAGL2:

Pleomorphic adenoma gene 2

IGF2:

Insulin-like growth factor 2

AZA:

5-Azacytidine

DAC:

5-Aza-2′-deoxycytidine

EGCG:

Epigallocatechin gallate

SLE:

Systemic lupus erythematosus

RARβ:

Retinoic acid receptor beta

MCF 7:

Michigan Cancer Foundation-7

PITX 2:

Paired-like homeodomain transcription factor 2

LAC:

Lung adenocarcinoma

LAT:

Linker for activation of T cells

HOXD3:

Homeobox D3

NFE2L3:

Nuclear factor (erythroid 2)-like factor 3

MDS:

Myelodysplastic syndrome

CRISPR:

Clustered regularly interspaced short palindromic repeats

PROTOC:

Proteolysis targeting chimeric

References

  1. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23–38. https://doi.org/10.1038/npp.2012.112.

    Article  CAS  Google Scholar 

  2. Wajed SA, Laird PW, DeMeester TR. DNA methylation: an alternative pathway to cancer. Ann Surg. 2001;234(1):10–20. https://doi.org/10.1097/00000658-200107000-00003.

    Article  CAS  Google Scholar 

  3. Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013;502(7472):472–9. https://doi.org/10.1038/nature12750.

    Article  CAS  Google Scholar 

  4. Cheishvili D, Boureau L, Szyf M. DNA demethylation and invasive cancer: implications for therapeutics. Br J Pharmacol. 2015. https://doi.org/10.1111/bph.12885.

    Article  Google Scholar 

  5. Bariol C, Suter C, Cheong K, Ku SL, Meagher A, Hawkins N, Ward R. The relationship between hypomethylation and CpG island methylation in colorectal neoplasia. Am J Pathol. 2003;162(4):1361–71. https://doi.org/10.1016/S0002-9440(10)63932-6.

    Article  CAS  Google Scholar 

  6. Butler JS, Dent SY. The role of chromatin modifiers in normal and malignant hematopoiesis. Blood. 2013;121(16):3076–84. https://doi.org/10.1182/blood-2012-10-451237.

    Article  CAS  Google Scholar 

  7. Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet. 2021;37(11):1012–27. https://doi.org/10.1016/j.tig.2021.05.002.

    Article  CAS  Google Scholar 

  8. Greger V, Passarge E, Höpping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet. 1989;83(2):155–8. https://doi.org/10.1007/BF00286709.

    Article  CAS  Google Scholar 

  9. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042–54. https://doi.org/10.1056/NEJMra023075.

    Article  CAS  Google Scholar 

  10. Scoumanne A, Chen X. Protein methylation: a new regulator of the p53 tumor suppressor. Histol histopathol. 2008. https://doi.org/10.14670/hh-23.1143.

    Article  Google Scholar 

  11. Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D, Baylin SB. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995;55(20):4525–30.

    CAS  Google Scholar 

  12. Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D. 5’ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1(7):686–92. https://doi.org/10.1038/nm0795-686.

    Article  CAS  Google Scholar 

  13. Baur AS, Shaw P, Burri N, Delacrétaz F, Bosman FT, Chaubert P. Frequent methylation silencing of p15(INK4b) (MTS2) and p16(INK4a) (MTS1) in B-cell and T-cell lymphomas. Blood. 1999;94(5):1773–81.

    Article  CAS  Google Scholar 

  14. Su J, Huang YH, Cui X, Wang X, Zhang X, Lei Y, Xu J, Lin X, Chen K, Lv J, Goodell MA, Li W. Homeobox oncogene activation by pan-cancer DNA hypermethylation. Genome Biol. 2018;19(1):108. https://doi.org/10.1186/s13059-018-1492-3.

    Article  CAS  Google Scholar 

  15. Peinado MA. Hypomethylation of DNA. Encycl Cancer. 2011. https://doi.org/10.1007/978-3-642-16483-5_2923.

    Article  Google Scholar 

  16. Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004;22(22):4632–42. https://doi.org/10.1200/JCO.2004.07.151.

    Article  CAS  Google Scholar 

  17. Spencer DH, Russler-Germain DA, Ketkar S, Helton NM, Lamprecht TL, Fulton RS, Fronick CC, O’Laughlin M, Heath SE, Shinawi M, Westervelt P, Payton JE, Wartman LD, Welch JS, Wilson RK, Walter MJ, Link DC, DiPersio JF, Ley TJ. CpG Island hypermethylation mediated by DNMT3A is a consequence of AML progression. Cell. 2017;168(5):801-816.e13. https://doi.org/10.1016/j.cell.2017.01.021.

    Article  CAS  Google Scholar 

  18. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O’Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. https://doi.org/10.1056/NEJMoa1005143.

    Article  CAS  Google Scholar 

  19. Russler-Germain DA, Spencer DH, Young MA, Lamprecht TL, Miller CA, Fulton R, Meyer MR, Erdmann-Gilmore P, Townsend RR, Wilson RK, Ley TJ. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell. 2014;25(4):442–54. https://doi.org/10.1016/j.ccr.2014.02.010.

    Article  CAS  Google Scholar 

  20. Liu Z, Khong HT. Demethylating agents in the treatment of cancer. Pharmaceuticals. 2010;3(7):2022–44. https://doi.org/10.3390/ph3072022.

    Article  CAS  Google Scholar 

  21. Zhang J, Yang C, Wu C, Cui W, Wang L. DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy. Cancers. 2020;12(8):2123. https://doi.org/10.3390/cancers12082123.

    Article  CAS  Google Scholar 

  22. Lin RK, Wu CY, Chang JW, Juan LJ, Hsu HS, Chen CY, Lu YY, Tang YA, Yang YC, Yang PC, Wang YC. Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res. 2010;70(14):5807–17. https://doi.org/10.1158/0008-5472.

    Article  Google Scholar 

  23. Kanai Y, Ushijima S, Nakanishi Y, Sakamoto M, Hirohashi S. Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. Cancer Lett. 2003;192(1):75–82. https://doi.org/10.1016/s0304-3835(02)00689-4.

    Article  CAS  Google Scholar 

  24. Huang L, Hu B, Ni J, Wu J, Jiang W, Chen C, Yang L, Zeng Y, Wan R, Hu G, Wang X. Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis. J Exp Clin Cancer Res. 2016;4(35):27. https://doi.org/10.1186/s13046-016-0301-7.

    Article  CAS  Google Scholar 

  25. Etoh T, Kanai Y, Ushijima S, Nakagawa T, Nakanishi Y, Sasako M, Kitano S, Hirohashi S. Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol. 2004;164(2):689–99. https://doi.org/10.1016/S0002-9440(10)63156-2.

    Article  CAS  Google Scholar 

  26. Zhang Y, Sun B, Huang Z, Zhao DW, Zeng Q. Shikonin Inhibites Migration and Invasion of Thyroid Cancer Cells by Downregulating DNMT1. Med Sci Monit. 2018;1(24):661–70. https://doi.org/10.12659/msm.908381.

    Article  CAS  Google Scholar 

  27. Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y, Sasaki H. Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood. 2001;97(5):1172–9. https://doi.org/10.1182/blood.v97.5.1172.

    Article  CAS  Google Scholar 

  28. Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S. Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Hepatology. 2001;33(3):561–8. https://doi.org/10.1053/jhep.2001.22507.

    Article  CAS  Google Scholar 

  29. Kanai Y, Ushijima S, Kondo Y, Nakanishi Y, Hirohashi S. DNA methyltransferase expression and DNA methylation of CPG islands and peri-centromeric satellite regions in human colorectal and stomach cancers. Int J Cancer. 2001;91(2):205–12. https://doi.org/10.1002/1097-0215(200002)9999:9999%3c::aid-ijc1040%3e3.0.co;2-2.

    Article  CAS  Google Scholar 

  30. Leonard S, Pereira M, Fox R, Gordon N, Yap J, Kehoe S, Luesley D, Woodman C, Ganesan R. Over-expression of DNMT3A predicts the risk of recurrent vulvar squamous cell carcinomas. Gynecol Oncol. 2016;143(2):414–20. https://doi.org/10.1016/j.ygyno.2016.09.001.

    Article  CAS  Google Scholar 

  31. Ma HS, Wang EL, Xu WF, Yamada S, Yoshimoto K, Qian ZR, Shi L, Liu LL, Li XH. Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine-5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas. Med Sci Monit. 2018;13(24):4841–50. https://doi.org/10.12659/MSM.910608.

    Article  Google Scholar 

  32. Yan XJ, Xu J, Gu ZH, Pan CM, Lu G, Shen Y, Shi JY, Zhu YM, Tang L, Zhang XW, Liang WX, Mi JQ, Song HD, Li KQ, Chen Z, Chen SJ. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011;43(4):309–15. https://doi.org/10.1038/ng.788.

    Article  CAS  Google Scholar 

  33. Kuck D, Caulfield T, Lyko F, Medina-Franco JL. Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. Mol Cancer Ther. 2010;9(11):3015–23. https://doi.org/10.1158/1535-7163.

    Article  Google Scholar 

  34. Lai SC, Su YT, Chi CC, Kuo YC, Lee KF, Wu YC, Lan PC, Yang MH, Chang TS, Huang YH. DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation. J Exp Clin Cancer Res. 2019;38(1):474. https://doi.org/10.1186/s13046-019-1442-2.

    Article  CAS  Google Scholar 

  35. Zhao L, Shou H, Chen L, Gao W, Fang C, Zhang P. Effects of ginsenoside Rg3 on epigenetic modification in ovarian cancer cells. Oncol Rep. 2019;41(6):3209–18. https://doi.org/10.3892/or.2019.7115.

    Article  CAS  Google Scholar 

  36. Roll JD, Rivenbark AG, Jones WD, Coleman WB. DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines. Mol Cancer. 2008;25(7):15. https://doi.org/10.1186/1476-4598-7-15.

    Article  CAS  Google Scholar 

  37. Gokul G, Gautami B, Malathi S, Sowjanya AP, Poli UR, Jain M, Ramakrishna G, Khosla S. DNA methylation profile at the DNMT3L promoter: a potential biomarker for cervical cancer. Epigenetics. 2007. https://doi.org/10.4161/epi.2.2.3692.

    Article  Google Scholar 

  38. Deng T, Kuang Y, Wang L, Li J, Wang Z, Fei J. An essential role for DNA methyltransferase 3a in melanoma tumorigenesis. Biochem Biophys Res Commun. 2009;387(3):611–6. https://doi.org/10.1016/j.bbrc.2009.07.093.

    Article  CAS  Google Scholar 

  39. Sun L, Hui AM, Kanai Y, Sakamoto M, Hirohashi S. Increased DNA methyltransferase expression is associated with an early stage of human hepatocarcinogenesis. Jpn J Cancer Res. 1997;88(12):1165–70. https://doi.org/10.1111/j.1349-7006.1997.tb00345.x.

    Article  CAS  Google Scholar 

  40. Palomeras S, Diaz-Lagares Á, Viñas G, Setien F, Ferreira HJ, Oliveras G, Crujeiras AB, Hernández A, Lum DH, Welm AL, Esteller M, Puig T. Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer. Breast Cancer Res. 2019;21(1):79. https://doi.org/10.1186/s13058-019-1160-x.

    Article  CAS  Google Scholar 

  41. He DX, Gu XT, Jiang L, Jin J, Ma X. A methylation-based regulatory network for microRNA 320a in chemoresistant breast cancer. Mol Pharmacol. 2014;86(5):536–47. https://doi.org/10.1124/mol.114.092759.

    Article  CAS  Google Scholar 

  42. Li M, Balch C, Montgomery JS, Jeong M, Chung JH, Yan P, Huang TH, Kim S, Nephew KP. Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer. BMC Med Genomics. 2009;8(2):34. https://doi.org/10.1186/1755-8794-2-34.

    Article  CAS  Google Scholar 

  43. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003. https://doi.org/10.1056/NEJMoa043331.

    Article  CAS  Google Scholar 

  44. Lemma RB, Fleischer T, Martinsen E, Ledsaak M, Kristensen V, Eskeland R, Gabrielsen OS, Mathelier A. Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers. Epigenetics Chromatin. 2022;15(1):13. https://doi.org/10.1186/s13072-022-00444-9.

    Article  CAS  Google Scholar 

  45. Ren J, Singh BN, Huang Q, Li Z, Gao Y, Mishra P, Hwa YL, Li J, Dowdy SC, Jiang SW. DNA hypermethylation as a chemotherapy target. Cell Signal. 2011;23(7):1082–93. https://doi.org/10.1016/j.cellsig.2011.02.003.

    Article  CAS  Google Scholar 

  46. Keil KP, Lein PJ. DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? Environ Epigenet. 2016. https://doi.org/10.1093/eep/dvv012.

    Article  Google Scholar 

  47. Li X, Shang E, Dong Q, Li Y, Zhang J, Xu S, Zhao Z, Shao W, Lv C, Zheng Y, Wang H, Lei X, Zhu B, Zhang Z. Small molecules capable of activating DNA methylation-repressed genes targeted by the p38 mitogen-activated protein kinase pathway. J Biol Chem. 2018;293(19):7423–36. https://doi.org/10.1074/jbc.RA117.000757.

    Article  CAS  Google Scholar 

  48. McCabe MT, Brandes JC, Vertino PM. Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res. 2009;15(12):3927–37. https://doi.org/10.1158/1078-0432.CCR-08-2784.

    Article  CAS  Google Scholar 

  49. Héberlé É, Bardet AF. Sensitivity of transcription factors to DNA methylation. Essays Biochem. 2019;63(6):727–41. https://doi.org/10.1042/EBC20190033.

    Article  Google Scholar 

  50. Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, Das PK, Kivioja T, Dave K, Zhong F, Nitta KR, Taipale M, Popov A, Ginno PA, Domcke S, Yan J, Schübeler D, Vinson C, Taipale J. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. 2017. https://doi.org/10.1126/science.aaj2239.

    Article  Google Scholar 

  51. Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev. 1993;3(2):226–31. https://doi.org/10.1016/0959-437x(93)90027-m.

    Article  CAS  Google Scholar 

  52. Prokhortchouk A, Hendrich B, Jørgensen H, Ruzov A, Wilm M, Georgiev G, Bird A, Prokhortchouk E. The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev. 2001;15(13):1613–8. https://doi.org/10.1101/gad.198501. (PMID: 11445535).

    Article  CAS  Google Scholar 

  53. Long HK, Blackledge NP, Klose RJ. ZF-CxxC domain-containing proteins, CpG islands and the chromatin connection. Biochem Soc Trans. 2013;41(3):727–40. https://doi.org/10.1042/BST20130028.

    Article  CAS  Google Scholar 

  54. Homson JP, Skene PJ, Selfridge J, Clouaire T, Guy J, Webb S, Kerr AR, Deaton A, Andrews R, James KD, Turner DJ, Illingworth R, Bird A. CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature. 2020. https://doi.org/10.1038/nature08924.

    Article  Google Scholar 

  55. Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016;30(7):733–50. https://doi.org/10.1101/gad.276568.115.

    Article  CAS  Google Scholar 

  56. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Schöler A, van Nimwegen E, Wirbelauer C, Oakeley EJ, Gaidatzis D, Tiwari VK, Schübeler D. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480(7378):490–5. https://doi.org/10.1038/nature10716.

    Article  CAS  Google Scholar 

  57. Gazave E, Lapébie P, Richards GS, Brunet F, Ereskovsky AV, Degnan BM, Borchiellini C, Vervoort M, Renard E. Origin and evolution of the Notch signalling pathway: an overview from eukaryotic genomes. BMC Evol Biol. 2009;13(9):249. https://doi.org/10.1186/1471-2148-9-249.

    Article  CAS  Google Scholar 

  58. Allenspach EJ, Maillard I, Aster JC, Pear WS. Notch signaling in cancer. Cancer Biol Ther. 2002. https://doi.org/10.4161/cbt.1.5.159.

    Article  Google Scholar 

  59. Aithal MG, Rajeswari N. Role of Notch signalling pathway in cancer and its association with DNA methylation. J Genet. 2013;92(3):667–75. https://doi.org/10.1007/s12041-013-0284-5.

    Article  CAS  Google Scholar 

  60. Lu J, Wilfred P, Korbie D, Trau M. Regulation of canonical oncogenic signaling pathways in cancer via DNA methylation. Cancers. 2020;12(11):3199. https://doi.org/10.3390/cancers12113199.

    Article  CAS  Google Scholar 

  61. Molinari F, Frattini M. Functions and regulation of the PTEN gene in colorectal cancer. Front Oncol. 2014;16(3):326. https://doi.org/10.3389/fonc.2013.00326.PMID:24475377;PMCID:PMC3893597.

    Article  Google Scholar 

  62. Tse JWT, Jenkins LJ, Chionh F, Mariadason JM. Aberrant DNA methylation in colorectal cancer: what should we target? Trends Cancer. 2017;3(10):698–712. https://doi.org/10.1016/j.trecan.2017.08.003.

    Article  CAS  Google Scholar 

  63. Liu X, Chen X, Zeng K, Xu M, He B, Pan Y, Sun H, Pan B, Xu X, Xu T, Hu X, Wang S. DNA-methylation-mediated silencing of miR-486-5p promotes colorectal cancer proliferation and migration through activation of PLAGL2/IGF2/β-catenin signal pathways. Cell Death Dis. 2018;9(10):1037. https://doi.org/10.1038/s41419-018-1105-9.

    Article  CAS  Google Scholar 

  64. Varela-Rey M, Woodhoo A, Martinez-Chantar ML, Mato JM, Lu SC. Alcohol, DNA methylation, and cancer. Alcohol Res. 2013;35(1):25–35.

    Google Scholar 

  65. Szyf M. Therapeutic implications of DNA methylation. Future Oncol. 2005;1(1):125–35. https://doi.org/10.1517/14796694.1.1.125.

    Article  CAS  Google Scholar 

  66. Feng LY, Chen CX, Li L. Hypermethylation of tumor suppressor genes is a risk factor for poor prognosis in ovarian cancer: A meta-analysis. Medicine. 2019. https://doi.org/10.1097/MD.0000000000014588.

    Article  Google Scholar 

  67. Gnyszka A, Jastrzebski Z, Flis S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 2013;33(8):2989–96.

    CAS  Google Scholar 

  68. Issa JP. DNA methylation as a therapeutic target in cancer. Clin Cancer Res. 2007;13(6):1634–7. https://doi.org/10.1158/1078-0432.CCR-06-2076.

    Article  CAS  Google Scholar 

  69. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20(1):85–93. https://doi.org/10.1016/0092-8674(80)90237-8.

    Article  CAS  Google Scholar 

  70. Stresemann C, Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008;123(1):8–13. https://doi.org/10.1002/ijc.23607.

    Article  CAS  Google Scholar 

  71. Leone G, Voso MT, Teofili L, Lübbert M. Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol. 2003;109(1):89–102. https://doi.org/10.1016/s1521-6616(03)00207-9.

    Article  CAS  Google Scholar 

  72. Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006;5(1):37–50. https://doi.org/10.1038/nrd1930.

    Article  CAS  Google Scholar 

  73. Baylin SB. DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol. 2005;2(Suppl 1):S4-11. https://doi.org/10.1038/ncponc0354.

    Article  CAS  Google Scholar 

  74. Cheng JC, Yoo CB, Weisenberger DJ, Chuang J, Wozniak C, Liang G, Marquez VE, Greer S, Orntoft TF, Thykjaer T, Jones PA. Preferential response of cancer cells to zebularine. Cancer Cell. 2004;6(2):151–8. https://doi.org/10.1016/j.ccr.2004.06.023.

    Article  CAS  Google Scholar 

  75. Pan Y, Liu G, Zhou F, Su B, Li Y. DNA methylation profiles in cancer diagnosis and therapeutics. Clin Exp Med. 2018;18(1):1–14. https://doi.org/10.1007/s10238-017-0467-0.

    Article  CAS  Google Scholar 

  76. Chuang JC, Yoo CB, Kwan JM, Li TW, Liang G, Yang AS, Jones PA. Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2’-deoxycytidine. Mol Cancer Ther. 2005;4(10):1515–20. https://doi.org/10.1158/1535-7163.MCT-05-0172.

    Article  CAS  Google Scholar 

  77. Brueckner B, Kuck D, Lyko F. DNA methyltransferase inhibitors for cancer therapy. Cancer J. 2007. https://doi.org/10.1097/PPO.0b013e31803c7245.

    Article  Google Scholar 

  78. Huang S, Stillson NJ, Sandoval JE, Yung C, Reich NO. A novel class of selective non-nucleoside inhibitors of human DNA methyltransferase 3A. Bioorg Med Chem Lett. 2021. https://doi.org/10.1016/j.bmcl.2021.127908.

    Article  Google Scholar 

  79. Li C, Zheng Y, Pu K, Zhao D, Wang Y, Guan Q, Zhou Y. A four-DNA methylation signature as a novel prognostic biomarker for survival of patients with gastric cancer. Cancer Cell Int. 2020;20(20):88. https://doi.org/10.1186/s12935-020-1156-8.

    Article  CAS  Google Scholar 

  80. Weiss G, Cottrell S, Distler J, Schatz P, Kristiansen G, Ittmann M, Haefliger C, Lesche R, Hartmann A, Corman J, Wheeler T. DNA methylation of the PITX2 gene promoter region is a strong independent prognostic marker of biochemical recurrence in patients with prostate cancer after radical prostatectomy. J Urol. 2009;181(4):1678–85. https://doi.org/10.1016/j.juro.2008.11.120.

    Article  CAS  Google Scholar 

  81. Xia W, Chen Q, Wang J, Mao Q, Dong G, Shi R, Zheng Y, Xu L, Jiang F. DNA methylation mediated silencing of microRNA-145 is a potential prognostic marker in patients with lung adenocarcinoma. Sci Rep. 2015;19(5):16901. https://doi.org/10.1038/srep16901.

    Article  CAS  Google Scholar 

  82. Wang J, Zhao H, Dong H, Zhu L, Wang S, Wang P, Ren Q, Zhu H, Chen J, Lin Z, Cheng Y, Qian B, Zhang Y, Jia R, Wu W, Lu J, Tan J. LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches. J Cancer. 2019;10(26):6726–37. https://doi.org/10.7150/jca.35641.

    Article  CAS  Google Scholar 

  83. Yi J, Wang ZW, Cang H, Chen YY, Zhao R, Yu BM, Tang XM. p16 gene methylation in colorectal cancers associated with Duke’s staging. World J Gastroenterol. 2001;7(5):722–5. https://doi.org/10.3748/wjg.v7.i5.722.

    Article  CAS  Google Scholar 

  84. Ottaviano YL, Issa JP, Parl FF, Smith HS, Baylin SB, Davidson NE. Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res. 1994;54(10):2552–5.

    CAS  Google Scholar 

  85. Zhang S, Zhang J, Zhang Q, Liang Y, Du Y, Wang G. Identification of prognostic biomarkers for bladder cancer based on DNA methylation profile. Front Cell Dev Biol. 2022. https://doi.org/10.3389/fcell.2021.817086.

    Article  Google Scholar 

  86. Swift-Scanlan T, Vang R, Blackford A, Fackler MJ, Sukumar S. Methylated genes in breast cancer: associations with clinical and histopathological features in a familial breast cancer cohort. Cancer Biol Ther. 2011;11(10):853–65. https://doi.org/10.4161/cbt.11.10.15177.

    Article  Google Scholar 

  87. Lai HC, Lin YW, Huang TH, Yan P, Huang RL, Wang HC. Identification of novel DNA methylation markers in cervical cancer. Int J Cancer. 2008;123(1):161–7.

    Article  CAS  Google Scholar 

  88. Eissa MAL, Lerner L, Abdelfatah E, Shankar N, Canner JK, Hasan NM, Yaghoobi V, Huang B, Kerner Z, Takaesu F, Wolfgang C, Kwak R, Ruiz M, Tam M, Pisanic TR 2nd, Iacobuzio-Donahue CA, Hruban RH, He J, Wang TH, Wood LD, Sharma A, Ahuja N. Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood. Clin Epigenetics. 2019;11(1):59. https://doi.org/10.1186/s13148-019-0650-0.

    Article  CAS  Google Scholar 

  89. Shi H, Guo J, Duff DJ, Rahmatpanah F, Chitima-Matsiga R, Al-Kuhlani M, Taylor KH, Sjahputera O, Andreski M, Wooldridge JE, Caldwell CW. Discovery of novel epigenetic markers in non-Hodgkin’s lymphoma. Carcinogenesis. 2007;28(1):60–70. https://doi.org/10.1093/carcin/bgl092.

    Article  CAS  Google Scholar 

  90. Liu S, Ren S, Howell P, Fodstad O, Riker AI. Identification of novel epigenetically modified genes in human melanoma via promoter methylation gene profiling. Pigment Cell Melanoma Res. 2008;21(5):545–58. https://doi.org/10.1111/j.1755-148X.2008.00484.x.

    Article  CAS  Google Scholar 

  91. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97. https://doi.org/10.1016/s0092-8674(04)00045-5.

    Article  CAS  Google Scholar 

  92. Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, Diverio D, Ammatuna E, Cimino G, Lo-Coco F, Grignani F, Nervi C. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell. 2007;12(5):457–66. https://doi.org/10.1016/j.ccr.2007.09.020.

    Article  CAS  Google Scholar 

  93. Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, Bozzoni I. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell. 2005;123(5):819–31. https://doi.org/10.1016/j.cell.2005.09.023.

    Article  CAS  Google Scholar 

  94. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125(2):315–26. https://doi.org/10.1016/j.cell.2006.02.041.

    Article  CAS  Google Scholar 

  95. Ball MP, Li JB, Gao Y, Lee JH, LeProust EM, Park IH, Xie B, Daley GQ, Church GM. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 2009;27(4):361–8. https://doi.org/10.1038/nbt.1533.

    Article  CAS  Google Scholar 

  96. Kanai Y. Genome-wide DNA methylation profiles in precancerous conditions and cancers. Cancer Sci. 2010;101(1):36–45. https://doi.org/10.1111/j.1349-7006.2009.01383.x.

    Article  CAS  Google Scholar 

  97. Kalari S, Pfeifer GP. Identification of driver and passenger DNA methylation in cancer by epigenomic analysis. Adv Genet. 2010;70:277–308. https://doi.org/10.1016/B978-0-12-380866-0.60010-1.

    Article  CAS  Google Scholar 

  98. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, Mohammad HP, Chen W, Daniel VC, Yu W, Berman DM, Jenuwein T, Pruitt K, Sharkis SJ, Watkins DN, Herman JG, Baylin SB. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007;39(2):237–42. https://doi.org/10.1038/ng1972.

    Article  CAS  Google Scholar 

  99. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C, Weisenberger DJ, Campan M, Young J, Jacobs I, Laird PW. Epigenetic stem cell signature in cancer. Nat Genet. 2007;39(2):157–8. https://doi.org/10.1038/ng1941.

    Article  CAS  Google Scholar 

  100. Kristensen LS, Hansen LL. PCR-based methods for detecting single-locus DNA methylation biomarkers in cancer diagnostics, prognostics, and response to treatment. Clin Chem. 2009;55(8):1471–83. https://doi.org/10.1373/clinchem.2008.121962.

    Article  CAS  Google Scholar 

  101. Reddy AN, Jiang WW, Kim M, Benoit N, Taylor R, Clinger J, Sidransky D, Califano JA. Death-associated protein kinase promoter hypermethylation in normal human lymphocytes. Cancer Res. 2003;63(22):7694–8.

    CAS  Google Scholar 

  102. Candiloro IL, Dobrovic A. Detection of MGMT promoter methylation in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter single nucleotide polymorphism. Cancer Prev Res. 2009;2(10):862–7. https://doi.org/10.1158/1940-6207.CAPR-09-0056.

    Article  CAS  Google Scholar 

  103. Issa JP. Epigenetic variation and human disease. J Nutr. 2002;132(8 Suppl):2388S-2392S. https://doi.org/10.1093/jn/132.8.2388S.

    Article  CAS  Google Scholar 

  104. Deng G, Chen A, Hong J, Chae HS, Kim YS. Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res. 1999;59(9):2029–33.

    CAS  Google Scholar 

  105. Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301(5895):89–92. https://doi.org/10.1038/301089a0.

    Article  CAS  Google Scholar 

  106. Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54(5):716–27. https://doi.org/10.1016/j.molcel.2014.05.015.

    Article  CAS  Google Scholar 

  107. Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33. https://doi.org/10.1038/nature09303.

    Article  CAS  Google Scholar 

  108. Karpf AR, Jones DA. Reactivating the expression of methylation silenced genes in human cancer. Oncogene. 2002;21(35):5496–503. https://doi.org/10.1038/sj.onc.1205602.

    Article  CAS  Google Scholar 

  109. Madore J, Strbenac D, Vilain R, Menzies AM, Yang JY, Thompson JF, Long GV, Mann GJ, Scolyer RA, Wilmott JS. PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma. Clin Cancer Res. 2016;22(15):3915–23. https://doi.org/10.1158/1078-0432.CCR-15-1714.

    Article  CAS  Google Scholar 

  110. Emran AA, Chatterjee A, Rodger EJ, Tiffen JC, Gallagher SJ, Eccles MR, Hersey P. Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy. Trends Immunol. 2019;40(4):328–44. https://doi.org/10.1016/j.it.2019.02.004.

    Article  CAS  Google Scholar 

  111. Smith CC, Beckermann KE, Bortone DS, De Cubas AA, Bixby LM, Lee SJ, Panda A, Ganesan S, Bhanot G, Wallen EM, Milowsky MI, Kim WY, Rathmell WK, Swanstrom R, Parker JS, Serody JS, Selitsky SR, Vincent BG. Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. J Clin Invest. 2018;128(11):4804–20. https://doi.org/10.1172/JCI121476.

    Article  Google Scholar 

  112. Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD. Epigenetic therapy in immune-oncology. Nat Rev Cancer. 2019;19(3):151–61. https://doi.org/10.1038/s41568-019-0109-9.

    Article  CAS  Google Scholar 

  113. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, Kotarski J, Tarkowski R, Dou Y, Cho K, Hensley-Alford S, Munkarah A, Liu R, Zou W. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527(7577):249–53. https://doi.org/10.1038/nature15520.

    Article  CAS  Google Scholar 

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Funding

This research was supported by the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Govt. of India (Sanction Order No. ECR/2016/000965), KOUSTAV SARKAR.

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  1. Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India

    Sannidhi Bhootra, Nandana Jill, Geetha Shanmugam, Sudeshna Rakshit & Koustav Sarkar

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SB contributed to investigation, data curation, writing of the original draft, and visualization; NJ contributed to investigation, data curation, writing of the original draft, and visualization; GS contributed to writing, reviewing, & editing of the manuscript; SR contributed to writing, reviewing, & editing of the manuscript; Koustav Sarkar contributed to conceptualization, writing, reviewing, & editing of the manuscript, supervision, project administration, and funding acquisition.

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Bhootra, S., Jill, N., Shanmugam, G. et al. DNA methylation and cancer: transcriptional regulation, prognostic, and therapeutic perspective. Med Oncol 40, 71 (2023). https://doi.org/10.1007/s12032-022-01943-1

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