Helicobacter pylori decreases p27 expression through the delta opioid receptor-mediated inhibition of histone acetylation within the p27 promoter

Abstract

Chronic Helicobacter pylori infection is associated with the decreased expression of the gastric tumour suppressor protein p27. Because transcription of the gene p27 may be regulated epigenetically through histone acetylation, which is mediated by G-protein coupled delta opioid receptor (DOR) stimulation, we examined whether H. pylori regulates the DOR/histone acetylation/p27 promoter pathway. The levels of acetylated histone and p300, a gene-specific histone acetyltransferase within the p27 promoter, were measured using ChIP assays. The expression of phospho-DOR was evaluated by Western blot and immunohistochemical analyses. Growth curves were constructed, and cell proliferation was assessed after BrdU incorporation. Low p27 expression in acutely H. pylori-infected AGS gastric epithelial cells and in chronically H. pylori-infected AGS-derived HS3C cells was associated with approximate 20% and 40% decreases in p27 mRNA expression, respectively, when compared to p27 mRNA levels in uninfected AGS parental cells. The low p27 mRNA levels following H. pylori infection were associated with a 15%–60% reduction in p27 promoter histone H4 acetylation. The recruitment of p300 to the p27 promoter was also markedly decreased by H. pylori infection. The expression of phospho-DOR was decreased by H. pylori infection in cell lines in vitro and in H. pylori-infected human gastric mucosa in vivo. The level of cellular p27 inversely correlated with cell proliferation in HS3C cells. These results demonstrate that H. pylori decreases p27 expression by modulating the DOR and thereby inhibiting histone acetylation of the p27 promoter. These findings link low gastric p27 expression levels with increased instances of gastric carcinogenesis associated with H. pylori infection.

FoxM1 is Overexpressed in Helicobacter pylori–Induced Gastric Carcinogenesis and Is Negatively Regulated by miR-370

“…However, P27 Kip1 inhibition and colony number were only partially reversed after knockdown of FoxM1 by its specific siRNA, which suggests other molecules involved in this process. One study showed that H. pylori decreased P27 Kip1 expression through delta opioid receptor-mediated inhibition of histone acetylation within the P27 Kip1 promoter (40). Other research confirmed the involvement of cytoplasmic mislocalization of P27 Kip1 induced by H. pylori in gastric cancer (41).…”

Methionine enkephalin (MENK) improves lymphocyte subpopulations in human peripheral blood of 50 cancer patients by inhibiting regulatory T cells (Tregs)

“…Many results both from our laboratory and from other institutes on MENK's function of upregulating immune system at suitable dose have been reported previously. [15][16][17][18][19][20][21] Our documented record showed that considerable work of approaches with MENK on its impact on immune cells in vitro and in vivo has been done in our laboratory. [7][8][9][10][11] There are predominantly mu, delta, and kappa-3 types of opioid receptors.…”

Gastrin-induced miR-222 promotes gastric tumor development by suppressing p27kip1

“…H. pylori infection decreases the expression of the cell cycle inhibitor protein p27 at both transcriptional and post-translational levels. H. pylori modulates the G-protein coupled delta opioid receptor (DOR) which regulates the histone acetylation of the p27 gene (CDKN1B) [49]. In addition cagA+ H. pylori strains decrease the transcription of p27 through activation of the PI3K/Akt pathway [50].…”