The Association of Methylation Status and Expression Level of MyoD1 with DNMT1 Expression Level in Breast Cancer Patients
-
Sahar Khojastehpour
,
Farshad Foroughi
,
Nematollah Gheibi
,
Zahra Mohammadi
,
Mohammad Hossein Ahmadi
,
Neda Nasirian
,
Amirhosein Maali
,
Mehdi Azad
Abstract
Background: Breast cancer (BC) is the most common malignancy in women worldwide. The methylation status of MyoD1, a tumor suppressor gene, is enrolled in various cancers, i.e., BC. Various studies showed the impact of MyoD1 epigenetic dysregulation in BC. This study aimed to investigate the methylation status and expression level of MyoD1 in BC patients and its association with the expression of DNMT1.
Materials and Methods: This case-control study was conducted on 30 cases (pathology-confirmed ductal carcinoma) and 18 controls (fibroadenoma and fibrocystic masses), referred to Velayat Hospital, Qazvin, Iran. The expression of the MyoD1 and DNMT1 and the promoter methylation of the MyoD1 were evaluated in tissue blocks of BC patient masses using qRT-PCR and MS-PCR assays, respectively. SPSS 24.0 was used to analyze the data.
Results: The MyoD1 promoter is hypermethylated in BC patients compared to controls (p =0.001). The expression level of MyoD1 in BC patients was significantly reduced compared to controls (fold change =0.13, p =0.042). In addition, in BC patients, the reduced expression level of MyoD1 was significantly associated with methylation of the MyoD1 promoter (p =0.001). There is no significant difference between the expression level of DNMT1 in BC patients and controls (p =0.197). A significant association is found between the expression of DNMT1 and the methylation status of the MyoD1 promoter (p =0.038).
Discussion: The expression level of MyoD1 is affected by the methylation status of the promoter of this gene. Moreover, the expression level and methylation status of MyoD1 are correlated with clinical parameters.
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16. Sebire NJ, Malone M. Myogenin and MyoD1 expression in paediatric rhabdomyosarcomas. J Clin Pathol. 2003;56(6):412-6.
17. Jeziorska DM, Murray RJS, De Gobbi M, et al. DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease. Proc Natl Acad Sci U S A. 2017;114(36):E7526-E35.
18. Jin W, Liu Y, Chen L, et al. Involvement of MyoD and c-myb in regulation of basal and estrogen-induced transcription activity of the BRCA1 gene. Breast Cancer Res Treat. 2011;125(3):699-713.
19. Xu XL, Yu J, Zhang HY, et al. Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis. World J Gastroenterol. 2004;10(23):3441-54.
20. Loaeza-Loaeza J, Illades-Aguiar B, Del Moral-Hernández O, et al. The CpG island methylator phenotype increases the risk of high-grade squamous intraepithelial lesions and cervical cancer. Clin Epigenetics. 2022;14(1):4.
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22. van Hoesel AQ, Sato Y, Elashoff DA, et al. Assessment of DNA methylation status in early stages of breast cancer development. Br J Cancer. 2013;108(10):2033-8.
23. Narasimhan M, Hong J, Atieno N, et al. Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells. Free Radic Biol Med. 2014;71:402-14.
24. Cha YJ, Kim HM, Koo JS. Expression of DNA methylation-related proteins in invasive lobular carcinoma of breast: comparison to invasive ductal carcinoma. Histol Histopathol. 2017;32(11):1175-85.
25. Li H, Liu JW, Sun LP, et al. A Meta-Analysis of the Association between DNMT1 Polymorphisms and Cancer Risk. Biomed Res Int. 2017;2017:3971259.
26. Rajabi H, Tagde A, Alam M, et al. DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells. Oncogene. 2016;35(50):6439-45.
27. Kankava K, Kvaratskhelia E, Abzianidze E. A study of the relationship between levels of methyltransferases in peripheral blood mononuclear cells and characteristics of tumor in patients with ductal invasive carcinoma of breast. Georgian Med News. 2016(259):31-5.
28. Neupane M, Clark AP, Landini S, et al. MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy. Cancer Discov. 2016;6(1):45-58.
29. Zhao L, Liu Y, Tong D, et al. MeCP2 Promotes Gastric Cancer Progression Through Regulating FOXF1/Wnt5a/beta-Catenin and MYOD1/Caspase-3 Signaling Pathways. EBioMedicine. 2017;16:87-100.
30. Chatterjee B, Wolff DW, Jothi M, et al. p38alpha MAPK disables KMT1A-mediated repression of myogenic differentiation program. Skelet Muscle. 2016;6:28.
31. Tierney MT, Aydogdu T, Sala D, et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat Med. 2014;20(10):1182-6.
32. Pan YC, Wang XW, Teng HF, et al. Wnt3a signal pathways activate MyoD expression by targeting cis-elements inside and outside its distal enhancer. Biosci Rep. 2015;35(2):e00180.
33. Muller HM, Widschwendter A, Fiegl H, et al. DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res. 2003;63(22):7641-5.
34. Duffy MJ, Napieralski R, Martens JW, et al. Methylated genes as new cancer biomarkers. Eur J Cancer. 2009;45(3):335-46.
35. Shan M, Yin H, Li J, et al. Detection of aberrant methylation of a six-gene panel in serum DNA for diagnosis of breast cancer. Oncotarget. 2016;7(14):18485-94.
2. Omidi Z, Koosha M, Nazeri N, et al. Status of breast cancer screening strategies and indicators in Iran: A scoping review. J Res Med Sci. 2022;27:21.
3. El-Kadiry AE, Rafei M, Shammaa R. Cell Therapy: Types, Regulation, and Clinical Benefits. Front Med (Lausanne). 2021;8:756029.
4. Moradi Z, Maali A, Shad JS, et al. Updates on Novel Erythropoiesis-Stimulating Agents: Clinical and Molecular Approach. Indian J Hematol Blood Transfus. 2020;36(1):26-36.
5. Biswas S, Rao CM. Epigenetics in cancer: Fundamentals and Beyond. Pharmacol Ther. 2017;173:118-34.
6. Maroufi F, Maali A, Abdollahpour-Alitappeh M, et al. CRISPR-mediated modification of DNA methylation pattern in the new era of cancer therapy. Epigenomics. 2020;12(20):1845-59.
7. Pal S, Tyler JK. Epigenetics and aging. Sci Adv. 2016;2(7):e1600584.
8. Brennan K. Blood DNA methylation biomarkers for breast cancer risk. Presented for the Ph.D., UK. Imperial College London. 2013.
9. Widschwendter M, Apostolidou S, Raum E, et al. Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study. PLoS One. 2008;3(7):e2656.
10. Di Ruscio A, Ebralidze AK, Benoukraf T, et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013;503(7476):371-6.
11. Rahmani T, Azad M, Chahardouli B, et al. Patterns of DNMT1 Promoter Methylation in Patients with Acute Lymphoblastic Leukemia. Int J Hematol Oncol Stem Cell Res. 2017;11(3):172-177.
12. Cheray M, Nadaradjane A, Bonnet P, et al. Specific inhibition of DNMT1/CFP1 reduces cancer phenotypes and enhances chemotherapy effectiveness. Epigenomics. 2014;6(3):267-75.
13. Tan W, Zhou W, Yu HG, et al. The DNA methyltransferase inhibitor zebularine induces mitochondria-mediated apoptosis in gastric cancer cells in vitro and in vivo. Biochem Biophys Res Commun. 2013;430(1):250-5.
14. Maali A, Ferdosi-Shahandashti E, Azad MJIJoB, Cancer. Drug switching, a creative approach to leukemia therapy. Iran J Blood Cancer. 2019;11(3):111-2.
15. Hernandez-Hernandez JM, Garcia-Gonzalez EG, Brun CE, et al. The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration. Semin Cell Dev Biol. 2017;72:10-8.
16. Sebire NJ, Malone M. Myogenin and MyoD1 expression in paediatric rhabdomyosarcomas. J Clin Pathol. 2003;56(6):412-6.
17. Jeziorska DM, Murray RJS, De Gobbi M, et al. DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease. Proc Natl Acad Sci U S A. 2017;114(36):E7526-E35.
18. Jin W, Liu Y, Chen L, et al. Involvement of MyoD and c-myb in regulation of basal and estrogen-induced transcription activity of the BRCA1 gene. Breast Cancer Res Treat. 2011;125(3):699-713.
19. Xu XL, Yu J, Zhang HY, et al. Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis. World J Gastroenterol. 2004;10(23):3441-54.
20. Loaeza-Loaeza J, Illades-Aguiar B, Del Moral-Hernández O, et al. The CpG island methylator phenotype increases the risk of high-grade squamous intraepithelial lesions and cervical cancer. Clin Epigenetics. 2022;14(1):4.
21. Cava C, Bertoli G, Castiglioni I. Integrating genetics and epigenetics in breast cancer: biological insights, experimental, computational methods and therapeutic potential. BMC Syst Biol. 2015;9:62.
22. van Hoesel AQ, Sato Y, Elashoff DA, et al. Assessment of DNA methylation status in early stages of breast cancer development. Br J Cancer. 2013;108(10):2033-8.
23. Narasimhan M, Hong J, Atieno N, et al. Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells. Free Radic Biol Med. 2014;71:402-14.
24. Cha YJ, Kim HM, Koo JS. Expression of DNA methylation-related proteins in invasive lobular carcinoma of breast: comparison to invasive ductal carcinoma. Histol Histopathol. 2017;32(11):1175-85.
25. Li H, Liu JW, Sun LP, et al. A Meta-Analysis of the Association between DNMT1 Polymorphisms and Cancer Risk. Biomed Res Int. 2017;2017:3971259.
26. Rajabi H, Tagde A, Alam M, et al. DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells. Oncogene. 2016;35(50):6439-45.
27. Kankava K, Kvaratskhelia E, Abzianidze E. A study of the relationship between levels of methyltransferases in peripheral blood mononuclear cells and characteristics of tumor in patients with ductal invasive carcinoma of breast. Georgian Med News. 2016(259):31-5.
28. Neupane M, Clark AP, Landini S, et al. MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy. Cancer Discov. 2016;6(1):45-58.
29. Zhao L, Liu Y, Tong D, et al. MeCP2 Promotes Gastric Cancer Progression Through Regulating FOXF1/Wnt5a/beta-Catenin and MYOD1/Caspase-3 Signaling Pathways. EBioMedicine. 2017;16:87-100.
30. Chatterjee B, Wolff DW, Jothi M, et al. p38alpha MAPK disables KMT1A-mediated repression of myogenic differentiation program. Skelet Muscle. 2016;6:28.
31. Tierney MT, Aydogdu T, Sala D, et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat Med. 2014;20(10):1182-6.
32. Pan YC, Wang XW, Teng HF, et al. Wnt3a signal pathways activate MyoD expression by targeting cis-elements inside and outside its distal enhancer. Biosci Rep. 2015;35(2):e00180.
33. Muller HM, Widschwendter A, Fiegl H, et al. DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res. 2003;63(22):7641-5.
34. Duffy MJ, Napieralski R, Martens JW, et al. Methylated genes as new cancer biomarkers. Eur J Cancer. 2009;45(3):335-46.
35. Shan M, Yin H, Li J, et al. Detection of aberrant methylation of a six-gene panel in serum DNA for diagnosis of breast cancer. Oncotarget. 2016;7(14):18485-94.
| Files | ||
| Issue | Vol 17, No 3 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v17i3.13303 | |
| Keywords | ||
| Methylation; Breast cancer; Epigenetics, Gene expression | ||
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How to Cite
1.
Khojastehpour S, Foroughi F, Gheibi N, Mohammadi Z, Ahmadi MH, Nasirian N, Maali A, Azad M. The Association of Methylation Status and Expression Level of MyoD1 with DNMT1 Expression Level in Breast Cancer Patients. Int J Hematol Oncol Stem Cell Res. 2023;17(3):133-144.
