Interaction of DNA demethylase and histone methyltransferase upregulates Nrf2 in 5-fluorouracil-resistant colon cancer cells.
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.
School of Medicine, Jeju National University, Jeju 63243, Republic of Korea.
Kyoung Ah
KA
Kang
School of Medicine, Jeju National University, Jeju 63243, Republic of Korea.
Mei Jing
MJ
Piao
School of Medicine, Jeju National University, Jeju 63243, Republic of Korea.
Yea Seong
YS
Ryu
School of Medicine, Jeju National University, Jeju 63243, Republic of Korea.
Hee Kyoung
HK
Kang
School of Medicine, Jeju National University, Jeju 63243, Republic of Korea.
Weon Young
WY
Chang
Department of Biochemistry, College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea.
Young Sam
YS
Keum
School of Medicine, Jeju National University, Jeju 63243, Republic of Korea.
Jin Won
JW
Hyun
D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
D006657:Histones; C497422:KMT2A protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051788:Myeloid-Lymphoid Leukemia Protein; D006861:Hydrogen Peroxide; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D008239:Lysine; D005472:Fluorouracil
5-fluorouracil-resistance; DNA demethylase; Nrf2 transcription factor; histone methyltransferase; oxidative stress