Epigenetic Mechanisms Underlying the Therapeutic Effects of Temozolomide in Glioma
Main Article Content
Abstract
Temozolomide remains the standard chemotherapeutic for glioblastoma multiforme, the most aggressive primary brain tumor. Traditionally, temozolomide has long been understood as a DNA alkylating agent that triggers cell death through O^6-methylguanine formation and subsequent mismatch repair-mediated apoptosis. However, emerging research has uncovered that temozolomide also functions as a dual epigenetic regulator. Beyond DNA methylation, temozolomide can modulate histone methylation patterns both through direct chemical modifications and indirect effects on histone-modifying enzyme activity. These mechanisms fundamentally reorganize chromatin architectures and alter gene expression programs within cancer cells. The combined genotoxic and epigenetic actions of temozolomide not only contribute to its anti-tumor effectiveness but also drive adaptive mechanisms of cancer cell resistance and recurrence. Understanding temozolomide’s capacity for epigenetic reprogramming and its impact on tumor microenvironment dynamics provides crucial insights for developing more effective treatment strategies. This knowledge supports the rationale for combination therapies that integrate temozolomide with epigenetic inhibitors, targeted enzyme modulators, or bioactive natural compounds alongside radiation therapy, potentially leading to significantly improved clinical outcomes for glioma patients.
Keywords:
Temozolomide, therapeutic benefit, DNA and histone methylation, Cell death pathways, epigenetic regulation
Article Details
How to Cite
WANG, Tieli.
Epigenetic Mechanisms Underlying the Therapeutic Effects of Temozolomide in Glioma.
Medical Research Archives, [S.l.], v. 13, n. 10, oct. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6955>. Date accessed: 06 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i10.6955.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. Schaff LR, Mellinghoff IK. Glioblastoma and Other Primary Brain Malignancies in Adults: A Review. JAMA. 2023;329(7):574-587. doi:10.1001/jama.20 23.0023
3. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-996. doi:10.1056/NEJMoa043330
4. Stupp R, Hegi ME, Mason WP, et al. 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. doi:10.1016/S1470-2045(09)7 0025-7
5. Kaina B. Temozolomide, Procarbazine and Nitrosoureas in the Therapy of Malignant Gliomas: Update of Mechanisms, Drug Resistance and Therapeutic Implications. J Clin Med. 2023;12(23): 7442. Published 2023 Nov 30. doi:10.3390/jcm12 237442
6. Roos WP, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332(2): 237-248. doi: 10.1016/j.canlet.2012.01.007
7. Fares J, Petrosyan E, Dmello C, Lukas RV, Stupp R, Lesniak MS. Rethinking metastatic brain cancer as a CNS disease. Lancet Oncol. 2025;26(2):e111-e121. doi:10.1016/S1470-2045(24)00430-3
8. Caldwell BA, Bartolomei MS. DNA methylation reprogramming of genomic imprints in the mammalian germline: A TET-centric view. Andrology. 2023;11 (5):884-890. doi:10.1111/andr.13303
9. Jezierzański M, Nafalska N, Stopyra M, et al. Temozolomide (TMZ) in the Treatment of Glioblastoma Multiforme-A Literature Review and Clinical Outcomes. Curr Oncol. 2024;31(7):3994-4002. Published 2024 Jul 12 doi:10.3390/curronco l31070296
10. Danson SJ, Middleton MR. Temozolomide: a novel oral alkylating agent. Expert Rev Anticancer Ther. 2001;1(1):13-19. doi:10.1586/14737140.1.1.13
11. Barczewski AM, Gurda D, Głodowicz P, Nowak S, Naskręt-Barciszewska MZ. A New Epigenetic Mechanism of Temozolomide Action in Glioma Cells. PLoS One. 2015;10(8):e0136669. Published 2015 Aug 26. doi: 10.1371/jour nal.pone.0136669
12. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006;31(2):89-97. doi: 10.1016/j.tibs.2005.12.008
13. Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, McKinney K, Tempst P, Prives C, Gamblin SJ, Barlev NA, Reinberg D. Regulation of p53 activity through lysine methylation. Nature. 2004 Nov 18;432(7015):353-60. doi: 10.1038/nature03117. Epub 2004 Nov 3. PMID: 15525938.
14. England B, Huang T, Karsy M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumour Biol. 2013;34(4):2063-2074. doi:10.1007/s13277-013-0871-3
15. He Y, Kaina B. Are There Thresholds in Glioblastoma Cell Death Responses Triggered by Temozolomide? Int J Mol Sci. 2019;20(7):1562. Published 2019 Mar 28.doi:10.3390/ijms20071562
16. Aasland D, Götzinger L, Hauck L, et al. Temozolomide Induces Senescence and Repression of DNA Repair Pathways in Glioblastoma Cells via Activation of ATR-CHK1, p21, and NF-κB. Cancer Res. 2019;79(1):99-113. doi: 10.1158/0008-5472.CAN-18-1733
17. Tomicic MT, Meise R, Aasland D, et al. Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM. Oncotarget. 2015;6(32):33755-33768. doi:10.1863 2/oncotarget.5274
18. Avci NG, Ebrahimzadeh-Pustchi S, Akay YM, et al. NF-κB inhibitor with Temozolomide results in significant apoptosis in glioblastoma via the NF-κB(p65) and actin cytoskeleton regulatory pathways. Sci Rep. 2020;10(1):13352. Published 2020 Aug 7 doi:10.1038/s41598-020-70392-5
19. Kaina B. Temozolomide, Procarbazine and Nitrosoureas in the Therapy of Malignant Gliomas: Update of Mechanisms, Drug Resistance and Therapeutic Implications. J Clin Med. 2023;12(23): 7442. Published 2023 Nov 30. doi:10.3390/jcm12 237442
20. Caporali S, Falcinelli S, Starace G, et al. DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system. Mol Pharmacol. 2004;66(3):478-491. doi:10.112 4/mol.66.3.
21. Pickard J., Diaz AJ, Mura, H., Nyuwen L, Coello, D., Saif, S., Nava, M., Gallo, J., and Wang T. Histone Methylation by Temozolomide; A Classic DNA Methylating Anticancer Drug. Supplements: World Biomedical frontiers, 2016.
22. Wang T, Pickard AJ, Gallo JM. Histone Methylation by Temozolomide; A Classic DNA Methylating Anticancer Drug. Anticancer Res. 2016;36(7):3289-3299.
23. Martinez, P, Bernal, R, Hills, R, and Wang, T. Anti-cancer drug, temozolomide, increased histone demethylase activity in breast cancer cells. 2024 Annual symposium of CSUPERB, Santa Clare, CA.
24. Füllgrabe J, Hajji N, Joseph B. Cracking the death code: apoptosis-related histone modifications. Cell Death Differ. 2010;17(8):1238-1243. doi:10.103 8/cdd.2010.58
25. Ruthenburg AJ, Allis CD, Wysocka J. Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell. 2007; 25(1):15-30. doi: 10.1016/j.molcel.2006.12.014
26. Shilatifard A. Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr Opin Cell Biol. 2008;20(3):341-348. doi: 10.1016/j.ceb.2008.03.019
27. Kouzarides T. Histone methylation in transcriptional control. Curr Opin Genet Dev. 2002; 12(2):198-209. doi:10.1016/s0959-437x(02)00287-3
28. Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 2005;6(11):838-849. doi:10.1038/nrm1761
29. Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell. 2012;48(4):491-507. doi: 10.1016/j.molcel.2012.11.006
30. Handel AE, Ebers GC, Ramagopalan SV. Epigenetics: molecular mechanisms and implications for disease. Trends Mol Med. 2010;16(1):7-16. doi: 10.1016/j.molmed.2009.11.003
31. Rajan PK, Udoh UA, Sanabria JD, et al. The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma. Int J Mol Sci. 2020;21(23):8894. Published 2020 Nov 24. doi:10.3390/ijms212 38894
32. Yu H, Lesch BJ. Functional Roles of H3K4 Methylation in Transcriptional Regulation. Mol Cell Biol. 2024;44(11):505-515. doi:10.1080/10985549.2 024.2388254
33. Wang H, Helin K. Roles of H3K4 methylation in biology and disease. Trends Cell Biol. 2025;35(2): 115-128. doi: 10.1016/j.tcb.2024.06.001
34. Heintzman ND, Hon GC, Hawkins RD, et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature. 2009;459(7243):108-112. doi:10.1038/nature07829
35. Herz HM, Mohan M, Garruss AS, et al. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 2012;26(23): 2604-2620. doi:10.1101/gad.201327.112
36. Briggs SD, Strahl BD. Unraveling heterochromatin. Nat Genet. 2002 Mar;30(3):241-2. doi: 10.1038/ng 0302-241. PMID: 11919553.
37. Fahrenkrog B. Histone modifications as regulators of life and death in Saccharomyces cerevisiae. Microb Cell. 2015 Dec 31;3(1):1-13. doi: 10.15698/mic201 6.01.472. PMID: 28357312; PMCID: PMC5354586.
38. Walter D, Matter A, Fahrenkrog B. Loss of histone H3 methylation at lysine 4 triggers apoptosis in Saccharomyces cerevisiae. PLoS Genet. 2014;10(1): e1004095. Published 2014 Jan 30. doi: 10.1371/jo urnal.pgen.1004095
39. Gehre M, Bunina D, Sidoli S, et al. Lysine 4 of histone H3.3 is required for embryonic stem cell differentiation, histone enrichment at regulatory regions and transcription accuracy. Nat Genet. 2020;52(3):273-282. doi:10.1038/s41588-020-0586-5
40. Wood K, Tellier M, Murphy S. DOT1L and H3K79 Methylation in Transcription and Genomic Stability. Biomolecules. 2018;8(1):11. Published 2018 Feb 27. doi:10.3390/biom8010011
41. Caldwell BA, Bartolomei MS. DNA methylation reprogramming of genomic imprints in the mammalian germline: A TET-centric view. Andrology. 2023;11(5):884-890. doi:10.1111/andr.13303
42. Cloos PA, Christensen J, Agger K, Helin K. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev. 2008;22(9):1115-1140. doi:10.1101/gad.1652908
43. Wysocka J, Milne TA, Allis CD. Taking LSD 1 to a new high. Cell. 2005;122(5):654-658. doi: 10.1016/j.c ell.2005.08.022
44. Shanower GA, Muller M, Blanton JL, Honti V, Gyurkovics H, Schedl P. Characterization of the grappa gene, the Drosophila histone H3 lysine 79 methyltransferases. Genetics. 2005;169(1):173-184. doi:10.1534/genetics.104.033191
45. Ooga M, Inoue A, Kageyama S, Akiyama T, Nagata M, Aoki F. Changes in H3K79 methylation during preimplantation development in mice. Biol Reprod. 2008;78(3):413-424. doi:10.1095/biolrepr od.107.063453
46. Lu Y, Chan YT, Tan HY, Li S, Wang N, Feng Y. Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy. Mol Cancer. 2020;19(1):79. Published 2020 Apr 27. doi:10.118 6/s12943-020-01197-3
47. Hwang YK, Lee DH, Lee EC, Oh JS. Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance. Cells. 2024;13(16):1332. doi:10.3390/cells13161332
48. Jeon M, Park J, Yang E, Baek HJ, Kim H. Regulation of autophagy by protein methylation and acetylation in cancer. J Cell Physiol. 2022;237 (1):13-28. doi:10.1002/jcp.30502
49. Lan T, Sun TT, Wei C, et al. Epigenetic Regulation of Ferroptosis in Central Nervous System Diseases. Mol Neurobiol. 2023;60(7):3584-3599. doi:10.1007/s1 2035-023-03267-1
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