Histone demethylase RBP2 induced by Helicobactor Pylori CagA participates in the malignant transformation of gastric epithelial cells

Abstract

Gastric epithelial cell malignant transformation induced by Helicobactor Pylori contributes to tumor development, but the underlying mechanisms for this remain unclear. Here we demonstrate that RBP2, a newly identified histone demethylase, can be induced by CagA via PI3K/AKT-Sp1 pathway depending on AKT phosphorylation. Sp1 directly binds to RBP2 promoter and enhances its expression then the upregulated RBP2 significantly increases Cyclin D1 transcription, which contributes to gastric epithelial cell malignant transformation. Further data indicate that knockdown of endogenous RBP2 dominantly inhibits gastric cancer (GC) development both in vitro and in vivo. In conclusion, this CagA- PI3K/AKT-Sp1-RBP2-Cyclin D1 pathway may serve as a novel mechanism for gastric epithelial cell malignant transformation and then gastric cancer (GC). Therefore, RBP2 may link chronic inflammation to tumor development and its inhibition may have potential therapeutic advantages.

Positive relationship between p42.3 gene and inflammation in chronic non‐atrophic gastritis

“…pylori also plays a role in immunomodulation by inhibiting both B‐cell and T‐cell lymphocyte proliferation that may induce a persistent inflammatory microenvironment . In addition to the induction of inflammatory cell infiltration, toxin produced by H. pylori affects the GES‐1 cells and can change the gene expression of the latter, damaging the integrity of gastric epithelial cells . Our data demonstrated that H. pylori infection significantly increased the expression of p42.3 gene in GES‐1 cells, which further emphasized the role of H. pylori as a class I carcinogen.…”

MicroRNAs and lncRNAs in senescence: A re‐view

“…In contrast, overexpression of RBP2 favors anchorage‐independent growth. It is suggested here that RBP2 may promote senescence bypass by H3K4 demethylation at promoters of cell cycle inhibitors .…”

Epigenetic roles in the malignant transformation of gastric mucosal cells

“…The infection of gastric epithelial cells with H. pylori leads to hyperacetylation of histone H4 [82], which induces the binding of histone H1 to ATP [83] and causes histone H3 dephosphorylation and deacetylation [41, 84]. These changes result in the abnormal expression of oncogenes and tumor suppressor genes [85, 86], which contributes to malignant transformation of gastric epithelial cells.…”