Oncotarget

Research Papers:

Epigenetic modification of TLR4 promotes activation of NF-κB by regulating methyl-CpG-binding domain protein 2 and Sp1 in gastric cancer

Tae Woo Kim, Seon-Jin Lee, Byung Moo Oh, Heesoo Lee, Tae Gi Uhm, Jeong-Ki Min, Young-Jun Park, Suk Ran Yoon, Bo-Yeon Kim, Jong Wan Kim, Yong-Kyung Choe and Hee Gu Lee _

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Oncotarget. 2016; 7:4195-4209. https://doi.org/10.18632/oncotarget.6549

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Abstract

Tae Woo Kim1,2,*, Seon-Jin Lee1,2,*, Byung Moo Oh1,2, Heesoo Lee1,2, Tae Gi Uhm1, Jeong-Ki Min3, Young-Jun Park4, Suk Ran Yoon4, Bo-Yeon Kim5, Jong Wan Kim6, Yong-Kyung Choe1, Hee Gu Lee1,2

1Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea

2Department of Biomolecular Science, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea

3Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea

4Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea

5World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Republic of Korea

6Department of Laboratory Medicine, College of Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea

*These authors have contributed equally to this work

Correspondence to:

Hee Gu Lee, e-mail: hglee@kribb.re.kr

Keywords: toll-like receptor 4, gastric cancer, Sp1, methyl-CpG-binding domain protein 2, methylation

Received: September 10, 2015     Accepted: November 23, 2015     Published: December 10, 2015

ABSTRACT

Toll-like receptor 4 (TLR4) is important in promoting the immune response in various cancers. Recently, TLR4 is highly expressed in a stage-dependent manner in gastric cancer, but the regulatory mechanism of TLR4 expression has been not elucidated it. Here, we investigated the mechanism underlying regulation of TLR4 expression through promoter methylation and histone modification between transcriptional regulation and silencing of the TLR4 gene in gastric cancer cells. Chromatin immunoprecipitation was carried out to screen for factors related to TLR4 methylation such as MeCP2, HDAC1, and Sp1 on the TLR4 promoter. Moreover, DNA methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-dC) induced demethylation of the TLR4 promoter and increased H3K4 trimethylation and Sp1 binding to reactivate silenced TLR4. In contrast, although the silence of TLR4 activated H3K9 trimethylation and MeCP2 complex, combined treatment with TLR4 agonist and 5-aza-dC upregulated H3K4 trimethylation and activated with transcription factors as Sp1 and NF-κB. This study demonstrates that recruitment of the MeCP2/HDAC1 repressor complex increases the low levels of TLR4 expression through epigenetic modification of DNA and histones on the TLR4 promoter, but Sp1 activates TLR4 high expression by hypomethylation and NF-κB signaling in gastric cancer cells.


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