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

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.

Geraniol alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis

“…NF-κB is a pivotal nuclear transcription factor in the inflammatory process and can be activated by TLR4 [ 23 , 24 ]. To further explore the anti-inflammatory mechanisms of GOH, we assessed the activation of the NF-κB pathway in LPS-stimulated RAW 264.7 cells.…”

Particulate matter exposure is associated with inflammatory gene methylation in obese subjects

“…In a recent study Kim T.W. et al suggest that the expression of TLR4 is suppressed due to epigenetic events such as methylation of DNA (Kim et al, 2015, Takahashi et al, 2009). …”

The Association between Gut Microbiota and Intestinal Toll-like Receptors Genes Expression in Adenomatous and Colorectal Cancerous patients

“…Following cDNA synthesis, to evaluate TLR2, TLR4 and TLR5 genes expression level, RT PCR and relative quantification method were performed by using Premix Ex Taq SYBR (Takara Bio-Japan) and Rotor Gene (QIAGEN-Germany). Real-time PCR was carried out by expressive primers (17,18) under the following conditions: 95°C for 5 s, 40 cycles of 95°C for 5 s, 60°C for 34 s, 95°C for 15 s, 60°C for 1 s and 60°C for 15s [14]. Amplification signals for samples were normalized by β-2microglobulin.…”