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

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

doi:10.18632/oncotarget.9745

Kyoung Ah Kang, Weon Young Chang + Show 5 more

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https://doi.org/10.18632/oncotarget.9745

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Journal: Oncotarget	Publication Date: May 31, 2016
Citations: 51	License type: cc-by

Affiliation: Jeju National University, Dongguk University

Abstract

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.

Highlights

IntroductionAcetylation, ubiquitination, and phosphorylation regulate gene expression programs
Histone modifications including methylation, acetylation, ubiquitination, and phosphorylation regulate gene expression programs
HDAC1 expression was decreased and HAT1 expression was increased in SNUC5/5-FUR cells compared to SNUC5 cells, resulting in increased H3K9 acetylation (H3K9Ac) (Figure 2A)

Summary

Introduction

Acetylation, ubiquitination, and phosphorylation regulate gene expression programs. The mixed-lineage leukemia (MLL) family of histone methyltransferases regulates gene expression by methylating lysine 4 of histone H3 (H3K4), which is associated with an active chromatin state [1]. Histone-lysine N-methyltransferase, SET, or MLL acts as the catalytic subunit of the protein complexes associated with the SET/COMPASS complex or MLL/COMPASS-like complex [2]. These subunits aid in complex assembly and recruitment to targets, and modulate the methyltransferase activity of the SET domain-containing subunits [1, 3]. TET proteins have been implicated in genome-wide DNA methylation control, gene expression regulation, cellular differentiation, and cancer development [6,7,8]

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