Helicobacter <i>pylori</i> induces promoter hypermethylation and downregulates gene expression of IRX1 transcription factor on human gastric mucosa

Vezatin (VEZT), an adherens junctions transmembrane protein, was identified as a putative tumor suppressor in our previous study. However, the role of VEZT in tumorigenesis remains elusive. We aimed to clarify its epigenetic regulation and biological functions in gastric cancer. In this study, we show that the expression level of VEZT is involved in lymphatic metastasis, depth of cancer invasion and TNM stage in 104 gastric cancer patients. Bisulfate sequencing polymerase chain reaction (BSP) methods showed that VEZT was hypermethylated in tissues and corresponding blood of gastric cancer patients compared with healthy controls. Helicobacter pylori (H. pylori) infection induces the methylation and silencing of VEZT in GES-1 cells. Restoring VEZT expression in MKN-45 and NCI-N87 gastric cancer cells inhibited growth, invasion and tumorigenesis in vitro and in vivo. Global microarray analysis was applied to analyze the molecular basis of the biological functions of VEZT after VEZT transfection combined with real-time PCR and chromatin immunoprecipitation assay. G protein-coupled receptor 56(GPR56), cell growth, cell division cycle 42(CDC42), migration/invasion and transcription factor 19(TCF19), cell cycle progression, were identified as direct VEZT target genes. TCF19, a novel target of VEZT, was functionally validated. Overexpression of TCF19 in MKN-45 cells increased cell cycle progress and growth ability. This study provides novel insight into the regulation of the VEZT gene, which could represent a potential target for therapeutic anti-cancer strategies.

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“…The remainder was H. pylori infection status was determined based on the rapid urease test as previously described [18]. …”

Section: Methodsmentioning

confidence: 99%

VEZT, a Novel Putative Tumor Suppressor, Suppresses the Growth and Tumorigenicity of Gastric Cancer

et al. 2013

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“…CpG island hypermethylation and genomic DNA hypomethylation are found in gastric tumors and premalignant lesions (Park et al, 2009), and H.pylori infection can induces aberrant CpG island hypermethylation in gastric mucosa (Nakajima et al, 2009;Park et al, 2009). Several reports indicated that accumulation of aberrant methylation in gastric mucosa produces a field for cancerization, and methylation levels correlate with gastric cancer risk (Guo et al, 2011;Wang et al, 2012). However, few studies have investigated the host factors, such as SNPs of DNA methyltransferases (DNMTs) gene, which may affect epigenetic regulation in gastric mucosa (Fan et al, 2010;Wu et al, 2012;Yang et al, 2012).…”

Section: Dnmt3amentioning

confidence: 99%

DNMT3a rs1550117 Polymorphism Association with Increased Risk of Helicobacter pylori Infection

Cao

Jia²,

Cao³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…The best-described examples are Helicobacter pylori [33] and uropathogenic Escherichia coli [34] where alterations of methylation profiles are responsible for characteristic changes in host gene expression. Wolbachia infection has also been shown to alter its host epigenetic makeup in a number of recent studies.…”

Section: Introductionmentioning

confidence: 99%

Infection with a Virulent Strain of Wolbachia Disrupts Genome Wide-Patterns of Cytosine Methylation in the Mosquito Aedes aegypti

Woolfit

Huttley

et al. 2013

PLoS ONE

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BackgroundCytosine methylation is one of several reversible epigenetic modifications of DNA that allow a greater flexibility in the relationship between genotype and phenotype. Methylation in the simplest models dampens gene expression by modifying regions of DNA critical for transcription factor binding. The capacity to methylate DNA is variable in the insects due to diverse histories of gene loss and duplication of DNA methylases. Mosquitoes like Drosophila melanogaster possess only a single methylase, DNMT2.DescriptionHere we characterise the methylome of the mosquito Aedes aegypti and examine its relationship to transcription and test the effects of infection with a virulent strain of the endosymbiont Wolbachia on the stability of methylation patterns.ConclusionWe see that methylation in the A. aegypti genome is associated with reduced transcription and is most common in the promoters of genes relating to regulation of transcription and metabolism. Similar gene classes are also methylated in aphids and honeybees, suggesting either conservation or convergence of methylation patterns. In addition to this evidence of evolutionary stability, we also show that infection with the virulent wMelPop Wolbachia strain induces additional methylation and demethylation events in the genome. While most of these changes seem random with respect to gene function and have no detected effect on transcription, there does appear to be enrichment of genes associated with membrane function. Given that Wolbachia lives within a membrane-bound vacuole of host origin and retains a large number of genes for transporting host amino acids, inorganic ions and ATP despite a severely reduced genome, these changes might represent an evolved strategy for manipulating the host environments for its own gain. Testing for a direct link between these methylation changes and expression, however, will require study across a broader range of developmental stages and tissues with methods that detect splice variants.

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Helicobacter pylori induces promoter hypermethylation and downregulates gene expression of IRX1 transcription factor on human gastric mucosa

Abstract: This study firstly demonstrated that H. pylori infection contributes to IRX1 promoter methylation on gastric mucosa.

Cited by 17 publications

References 34 publications

VEZT, a Novel Putative Tumor Suppressor, Suppresses the Growth and Tumorigenicity of Gastric Cancer

VEZT, a Novel Putative Tumor Suppressor, Suppresses the Growth and Tumorigenicity of Gastric Cancer

DNMT3a rs1550117 Polymorphism Association with Increased Risk of Helicobacter pylori Infection

Infection with a Virulent Strain of Wolbachia Disrupts Genome Wide-Patterns of Cytosine Methylation in the Mosquito Aedes aegypti

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