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J Cancer 2021; 12(9):2673-2686. doi:10.7150/jca.52378 This issue Cite

Research Paper

Promoter hypermethylation of early B cell factor 1 (EBF1) is associated with cholangiocarcinoma progression

Napat Armartmuntree1,2, Apinya Jusakul2,3, Chadamas Sakonsinsiri1,2, Watcharin Loilome1,2, Somchai Pinlaor2,4, Piti Ungarreevittaya2,5, Chern Han Yong6, Anchalee Techasen2,3, Kanokwan Imtawil1, Ratthaphol Kraiklang7, Nattawan Suwannakul8, Waleeporn Kaewlert1,2, Timpika Chaiprasert1,2, Raynoo Thanan1,2✉, Mariko Murata8✉

1. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
2. Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
3. Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
4. Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
5. Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
6. Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore.
7. Faculty of Public Health, Khon Kaen University, Khon Kaen 40002, Thailand.
8. Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514-8507, Japan.

✉ Corresponding authors: Dr. Raynoo Thanan, Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Tel/Fax: 66 43 348 386; E-mail: raynooac.th; Professor Mariko Murata, Department of Environmental and Mo More

Citation:
Armartmuntree N, Jusakul A, Sakonsinsiri C, Loilome W, Pinlaor S, Ungarreevittaya P, Yong CH, Techasen A, Imtawil K, Kraiklang R, Suwannakul N, Kaewlert W, Chaiprasert T, Thanan R, Murata M. Promoter hypermethylation of early B cell factor 1 (EBF1) is associated with cholangiocarcinoma progression. J Cancer 2021; 12(9):2673-2686. doi:10.7150/jca.52378. https://www.jcancer.org/v12p2673.htm
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Abstract

Graphic abstract

DNA hypermethylation in a promoter region causes gene silencing via epigenetic changes. We have previously reported that early B cell factor 1 (EBF1) was down-regulated in cholangiocarcinoma (CCA) tissues and related to tumor progression. Thus, we hypothesized that the DNA hypermethylation of EBF1 promoter would suppress EBF1 expression in CCA and induce its progression. In this study, the DNA methylation status of EBF1 and mRNA expression levels were analyzed in CCA and normal bile duct (NBD) tissues using a publicly available database of genome-wide association data. The results showed that the DNA methylation of EBF1 promoter region was significantly increased in CCA tissues compared with those of NBD. The degree of methylation was negatively correlated with EBF1 mRNA expression levels. Using methylation-specific PCR technique, the DNA methylation rates of EBF1 promoter region were investigated in CCA tissues (n=72). CCA patients with high methylation rates of EBF1 promoter region in the tumor tissues (54/72) had a poor prognosis. Higher methylation rates of EBF1 promoter region have shown in all CCA cell lines than that of an immortal cholangiocyte cell line (MMNK1). Upon treatment with the DNA methyltransferase inhibitor 5-Aza-dC, increased EBF1 expression levels and reduced DNA methylation rates were observed in CCA cells. Moreover, restoration of EBF1 expression in CCA cells led to inhibition of cell growth, migration and invasion. In addition, RNA sequencing analysis suggested that EBF1 is involved in suppression of numerous pathways in cancer. Taken together, DNA hypermethylation in the EBF1 promoter region suppresses EBF1 expression and induces CCA progression with aggressive clinical outcomes.

Keywords: cholangiocarcinoma, DNA methylation, EBF1, tumor progression, epigenetics

Citation styles

APA
Armartmuntree, N., Jusakul, A., Sakonsinsiri, C., Loilome, W., Pinlaor, S., Ungarreevittaya, P., Yong, C.H., Techasen, A., Imtawil, K., Kraiklang, R., Suwannakul, N., Kaewlert, W., Chaiprasert, T., Thanan, R., Murata, M. (2021). Promoter hypermethylation of early B cell factor 1 (EBF1) is associated with cholangiocarcinoma progression. Journal of Cancer, 12(9), 2673-2686. https://doi.org/10.7150/jca.52378.

ACS
Armartmuntree, N.; Jusakul, A.; Sakonsinsiri, C.; Loilome, W.; Pinlaor, S.; Ungarreevittaya, P.; Yong, C.H.; Techasen, A.; Imtawil, K.; Kraiklang, R.; Suwannakul, N.; Kaewlert, W.; Chaiprasert, T.; Thanan, R.; Murata, M. Promoter hypermethylation of early B cell factor 1 (EBF1) is associated with cholangiocarcinoma progression. J. Cancer 2021, 12 (9), 2673-2686. DOI: 10.7150/jca.52378.

NLM
Armartmuntree N, Jusakul A, Sakonsinsiri C, Loilome W, Pinlaor S, Ungarreevittaya P, Yong CH, Techasen A, Imtawil K, Kraiklang R, Suwannakul N, Kaewlert W, Chaiprasert T, Thanan R, Murata M. Promoter hypermethylation of early B cell factor 1 (EBF1) is associated with cholangiocarcinoma progression. J Cancer 2021; 12(9):2673-2686. doi:10.7150/jca.52378. https://www.jcancer.org/v12p2673.htm

CSE
Armartmuntree N, Jusakul A, Sakonsinsiri C, Loilome W, Pinlaor S, Ungarreevittaya P, Yong CH, Techasen A, Imtawil K, Kraiklang R, Suwannakul N, Kaewlert W, Chaiprasert T, Thanan R, Murata M. 2021. Promoter hypermethylation of early B cell factor 1 (EBF1) is associated with cholangiocarcinoma progression. J Cancer. 12(9):2673-2686.

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