Volume 9, Issue 1 (Vol.9 No.1 Apr 2020)                   rbmb.net 2020, 9(1): 33-39 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Taheri Z, Asadzadeh Aghdaei H, Irani S, Modarressi M H, Noormohammadi Z. Evaluation of the Epigenetic Demethylation of NRF2, a Master Transcription Factor for Antioxidant Enzymes, in Colorectal Cancer. rbmb.net. 2020; 9 (1) :33-39
URL: http://rbmb.net/article-1-426-en.html
Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Abstract:   (307 Views)
Background: Epigenetic changes in CpG islands of the promoter regions of homeostasis-related genes, including nuclear factor erythroid 2-related factor 2 (NRF2), have been shown to hold a significant role in the development of colorectal cancer. Therefore, we aimed to examine the DNA demethylation pattern of the NRF2 promoter region in cancerous lesions from patients with colorectal cancer and the association of methylation status with clinicopathological features in the Iranian population.

Methods: In this cross-sectional study, 114 colorectal tissue samples were collected. These samples included: 34 tumour tissue samples, 60 precancerous polyps, and 20 normal tissue samples. The promoter methylation status of the NRF2 gene was examined using methylation-specific PCR. Additionally, the relationship between the methylation status and the clinicopathological features was investigated.

Results: The frequency of NRF2 demethylation in the tumour samples was significantly higher compared to the polyp tissues (p= 0.003) and normal tissue (p= 0.009), indicating that cancerous colorectal tissues exhibit increased demethylation of the NRF2 promoter. After examining the demethylation status of tissue samples, the clinicopathological features were compared to the demethylation results. No significant association was found between NRF2 promoter demethylation and the clinicopathological features of patient samples.

Conclusions: Our findings suggest that the epigenetic modifications leading to NRF2 demethylation found in colorectal tumour samples may contribute to cancer progression from precancerous polyps to cancerous lesions.
Full-Text [PDF 303 kb]   (115 Downloads)    
Type of Article: Original Article | Subject: Molecular Biology
Received: 2019/11/28 | Accepted: 2019/12/15 | Published: 2020/05/19

1. 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29. [DOI:10.3322/caac.21208]
2. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525-32. [DOI:10.1056/NEJM198809013190901]
3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90. [DOI:10.3322/caac.20107]
4. Azadeh S, Reza FS, Sara A, Mohsen V, Bijan M-D, Zali ZR. Four years incidence rate of colorectal cancer in Iran: a survey of national cancer registry data-implications for screening. Asian Pac J Cancer Prev. 2012;13(6):2695-8. [DOI:10.7314/APJCP.2012.13.6.2695]
5. Carmona FJ, Esteller M. Epigenomics of human colon cancer. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2010;693(1-2):53-60. [DOI:10.1016/j.mrfmmm.2010.07.007]
6. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27-36. [DOI:10.1093/carcin/bgp220]
7. Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357(6348):eaal2380. [DOI:10.1126/science.aal2380]
8. Bryan HK, Olayanju A, Goldring CE, Park BK. The Nrf2 cell defence pathway: Keap1-dependent and-independent mechanisms of regulation. Biochemical pharmacol. 2013;85(6):705-17. [DOI:10.1016/j.bcp.2012.11.016]
9. Menegon S, Columbano A, Giordano S. The dual roles of NRF2 in cancer. Trends Mol Med. 2016;22(7):578-593. [DOI:10.1016/j.molmed.2016.05.002]
10. Nioi P, Nguyen T. A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun. 2007;362(4):816-21. [DOI:10.1016/j.bbrc.2007.08.051]
11. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS medicine. 2006;3(10):e420. [DOI:10.1371/journal.pmed.0030420]
12. Ji L, Wei Y, Jiang T, Wang S. Correlation of Nrf2, NQO1, MRP1, cmyc and p53 in colorectal cancer and their relationships to clinicopathologic
13. features and survival. International journal of clinical and experimental pathology. 2014;7(3):1124-31.
14. Guo Y, Yu S, Zhang C, Kong A-NT. Epigenetic regulation of Keap1-Nrf2 signaling. Free Radical Biology and Medicine. 2015;88(Pt B):337-349. [DOI:10.1016/j.freeradbiomed.2015.06.013]
15. Tanzer M, Balluff B, Distler J, Hale K, Leodolter A, Rocken C, et al. Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions. PLoS One. 2010;5(2):e9061. [DOI:10.1371/journal.pone.0009061]
16. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology. 2010;138(6):2029-2043.e10. [DOI:10.1053/j.gastro.2010.01.057]
17. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471-4. [DOI:10.1245/s10434-010-0985-4]
18. Porcellini E, Laprovitera N, Riefolo M, Ravaioli M, Garajova I, Ferracin M. Epigenetic and epitranscriptomic changes in colorectal cancer: Diagnostic, prognostic, and treatment implications. Cancer Lett. 2018;419:84-95. [DOI:10.1016/j.canlet.2018.01.049]
19. Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011;25 (10):1010-22. [DOI:10.1101/gad.2037511]
20. Garnier D, Magnus N, D'Asti E, Hashemi M, Meehan B, Milsom C, et al. Genetic pathways linking hemostasis and cancer. Thromb Res. 2012;129 Suppl 1:S22-S9. [DOI:10.1016/S0049-3848(12)70012-9]
21. Sadeghi MR, Jeddi F, Soozangar N, Somi MH, Samadi N. The role of Nrf2-Keap1 axis in colorectal cancer, progression, and chemoresistance. Tumour Biol. 2017;39 (6):1010428317705510. [DOI:10.1177/1010428317705510]
22. Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 2018;98(3):1169-1203. [DOI:10.1152/physrev.00023.2017]
23. Kobayashi M, Yamamoto M. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal. 2005;7(3-4):385-94. [DOI:10.1089/ars.2005.7.385]
24. Hayes JD, McMahon M. The double-edged sword of Nrf2: subversion of redox homeostasis during the evolution of cancer. Mol Cell. 2006;21(6):732-4. [DOI:10.1016/j.molcel.2006.03.004]
25. Stacy DR, Ely K, Massion PP, Yarbrough WG, Hallahan DE, Sekhar KR, et al. Increased expression of nuclear factor E2 p45- related factor 2 (NRF2) in head and neck squamous cell carcinomas. Head Neck. 2006;28(9):813-8. [DOI:10.1002/hed.20430]
26. Zheng H, Nong Z, Lu G. Correlation between nuclear factor E2-related factor 2 expression and gastric cancer progression. Medical science monitor: international medical journal of experimental and clinical research. 2015;21:2893-2899. [DOI:10.12659/MSM.894467]
27. Wang J, Zhang M, Zhang L, Cai H, Zhou S, Zhang J, et al. Correlation of Nrf2, HO-1, and MRP3 in gallbladder cancer and their relationships to clinicopathologic features and survival. J Surg Res. 2010;164 (1):e99-105. [DOI:10.1016/j.jss.2010.05.058]
28. Kang KA, Hyun JW. Oxidative stress, Nrf2, and epigenetic modification contribute to anticancer drug resistance. Toxicol Res. 2017;33(1):1-5. [DOI:10.5487/TR.2017.33.1.001]
29. Yu S, Khor TO, Cheung KL, Li W, Wu TY, Huang Y, et al. Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP mice. PloS one. 2010;5(1):e8579. [DOI:10.1371/journal.pone.0008579]
30. Akhdar H, Loyer P, Rauch C, Corlu A, Guillouzo A, Morel F. Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells. Eur J Cancer. 2009;45(12):2219-27. [DOI:10.1016/j.ejca.2009.05.017]
31. Arlt A, Bauer I, Schafmayer C, Tepel J, Muerkoster SS, Brosch M, et al. Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (Nrf2). Oncogene. 2009;28(45):3983-96. [DOI:10.1038/onc.2009.264]
32. Zhao XQ, Zhang YF, Xia YF, Zhou ZM, Cao YQ. Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells. Oncol Lett. 2015;10(3):1287-1292. [DOI:10.3892/ol.2015.3468]

Add your comments about this article : Your username or Email:

Send email to the article author

© 2015 All Rights Reserved | Reports of Biochemistry and Molecular Biology

Designed & Developed by : Yektaweb