Elevated Expression of DNA Methyltransferases and Enhancer of Zeste Homolog 2 in <b><i>Helicobacter pylori</i></b> - Gastritis and Gastric Carcinoma

Abstract

&lt;b&gt;&lt;i&gt;Aim:&lt;/i&gt;&lt;/b&gt; The aim of this study was to study the role of key epigenetic regulators pertaining to DNA methylation and histone-modification systems in &lt;i&gt;Helicobacter pylori&lt;/i&gt; (HP)-associated gastritis and gastric carcinogenesis. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; The expression of DNA methyltransferase (DNMT-1, 3A, and 3B) and the catalytic subunit of polycomb repressive complex-2 (enhancer of zeste homolog 2 [EZH2]) in gastric carcinomas (&lt;i&gt;n&lt;/i&gt; = 104), mucosa adjacent to carcinoma (&lt;i&gt;n&lt;/i&gt; = 104), HP-associated gastritis (&lt;i&gt;n&lt;/i&gt; = 95), and histologically normal mucosa (&lt;i&gt;n&lt;/i&gt; = 31) was assessed by immunohistochemistry and qRT-PCR. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The expression of all 3 DNMTs and EZH2 was significantly higher in HP-associated gastritis and carcinoma cases than in those with adjacent and normal mucosa. The expression of DNMT-1 and 3B was maximum in HP-associated gastritis. DNMT-3A showed higher expression in carcinoma-adjacent mucosa than in normal mucosa. Interestingly, the expression of EZH2 was higher in cases of HP-associated gastritis with metaplasia than in those without metaplasia and also in cases of intestinal type of adenocarcinoma. Significant positive correlation of EZH2 was identified with DNMT-1, DNMT-3A, and DNMT-3B. However, none of these markers was associated with survival outcome. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; This study establishes an important role of the key epigenetic regulators in the pathogenesis of both HP-associated gastritis and gastric carcinoma. Higher expression of all the epigenetic markers in the gastritis and their persistence in the carcinoma point toward their implications in HP-driven gastric carcinogenesis. Further, an inter-relation between the 2 arms of epigenetics, namely, DNA methylation and histone-modification in the pathogenesis of gastric carcinoma, is also documented. Given the reversibility of epigenetic phenomenon, these molecules may be of important therapeutic use.

Gastric Cancer in the Era of Epigenetics

“…DNMTs are pivotal contributors to the process of DNA methylation. Previous studies have shown elevated levels of DNMT-1- and DNMTs-3A/3B-protein expression in both HP-induced gastritis and gastric carcinomas [ 162 , 163 ]. Hedayati et al (2022), presented a correlation between Hp pathogenicity and increased DNMT1-expression levels [ 164 ], whereas Song et al (2020) identified a novel epigenetic signature in gastrointestinal adenocarcinomas.…”

“…EZH2-expression levels were notably higher in cases of metaplasia and exhibited a positive correlation with DNMT-expression levels. Epigenetic modifications can be reversed, thus targeting DNMTs and EZH2 could offer a promising therapeutic approach for gastric carcinoma [ 163 ]. Numerous inhibitors targeting DNMTs and EZH2 are examined to assess their potential efficacy in treating various malignancies [ 166 , 167 ].…”

Helicobacter pylori-induced NF-κB: trailblazer for gastric pathophysiology

“…Transformation is characterized by a defined epigenome [69]. There exists ample evidence that H. pylori infection leads to aberrant epigenetic modifications, inducing a CpG island methylator phenotype (CIMP) [70] and that these modifications contribute to gene regulation [25,27,71,72] and to the development of GC [73][74][75][76]. The impact of a single methylation in a position adjacent to the NF-B binding site on the function of NF-B has been shown recently [77].…”