Research Papers:

Interaction of DNA demethylase and histone methyltransferase upregulates Nrf2 in 5-fluorouracil-resistant colon cancer cells

Kyoung Ah Kang _, Mei Jing Piao, Yea Seong Ryu, Hee Kyoung Kang, Weon Young Chang, Young Sam Keum and Jin Won Hyun

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Oncotarget. 2016; 7:40594-40620. https://doi.org/10.18632/oncotarget.9745

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Kyoung Ah Kang1, Mei Jing Piao1, Yea Seong Ryu1, Hee Kyoung Kang1, Weon Young Chang1, Young Sam Keum2, Jin Won Hyun1

1School of Medicine, Jeju National University, Jeju 63243, Republic of Korea

2Department of Biochemistry, College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea

Correspondence to:

Jin Won Hyun, email: [email protected]

Keywords: Nrf2 transcription factor, DNA demethylase, histone methyltransferase, 5-fluorouracil-resistance, oxidative stress

Received: January 15, 2016     Accepted: May 09, 2016     Published: May 31, 2016


We recently reported that DNA demethylase ten-eleven translocation 1 (TET1) upregulates nuclear factor erythroid 2-related factor 2 (Nrf2) in 5-fluorouracil-resistant colon cancer cells (SNUC5/5-FUR). In the present study, we examined the effect of histone modifications on Nrf2 transcriptional activation. Histone deacetylase (HDAC) and histone acetyltransferase (HAT) were respectively decreased and increased in SNUC5/5-FUR cells as compared to non-resistant parent cells. Mixed-lineage leukemia (MLL), a histone methyltransferase, was upregulated, leading to increased trimethylation of histone H3 lysine 4, while G9a was downregulated, leading to decreased dimethylation of histone H3 lysine 9. siRNA-mediated MLL knockdown decreased levels of Nrf2 and HO-1 to a greater extent than did silencing HAT1. Host cell factor 1 (HCF1) was upregulated in SNUC5/5-FUR cells, and we observed interaction between HCF1 and MLL. Upregulation of O-GlcNAc transferase (OGT), an activator of HCF1, was also associated with HCF1-MLL interaction. In SNUC5/5-FUR cells, a larger fraction of OGT was bound to TET1, which recruits OGT to the Nrf2 promoter region, than in SNUC5 cells. These findings indicate that SNUC5/5-FUR cells are under oxidative stress, which induces expression of histone methylation-related proteins as well as DNA demethylase, leading to upregulation of Nrf2 and 5-FU resistance.

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