The polycomb group protein EZH2 induces epithelial–mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter

Abstract

BackgroundThe influences of oncogenic Ezh2 on the progression and prognosis of gastric cancer (GC) and the underlying mechanisms are still poorly understood. Here, we aimed at investigating clinicopathological significance of Ezh2 in GC and the mechanisms underlying its function in GC development.MethodsThe expression level of Ezh2 was determined by qRT-PCR, immunoblot, and immunohistochemistry analysis in 156 pairs of GC tissues and adjacent normal gastric mucosa tissues. The biological functions of Ezh2 were assessed by in vitro and in vivo functional experiments. Chromatin immunoprecipitation (ChIP), luciferase, and Western blotting analyses were utilized to identify the relationship between Ezh2 and the PTEN/Akt signaling.ResultsThe expression of Ezh2 was higher in gastric cancer tissues in comparison with para-nontumorous epithelium. High expression of Ezh2 was associated with more aggressive biological behavior and poor prognosis in GC. In vitro studies indicated that Ezh2 promoted GC cells’ proliferation and clonogenicity. Besides, Ezh2 led to the acquisition of epithelial–mesenchymal transition (EMT) phenotype of GC cells and enhanced GC cell migration and invasion capacity. In particular, Ezh2 strengthened sphere-forming capacity of GC cells, indicating its role in the enrichment of GC stem cells. Furthermore, we found that PTEN/Akt signaling contributed to the effects of Ezh2 on cancer stem cells (CSC) and EMT phenotype in GC cells, and blocking PTEN signaling significantly rescued the effects of Ezh2.ConclusionsTaken together, Ezh2 has a central role in regulating diverse aspects of the pathogenesis of GC in part by involving PTEN/Akt signaling, indicating that it could be an independent prognostic factor and potential therapeutic target.Electronic supplementary materialThe online version of this article (10.1186/s13045-017-0547-3) contains supplementary material, which is available to authorized users.

Exosome-transmitted lncRNA UFC1 promotes non-small-cell lung cancer progression by EZH2-mediated epigenetic silencing of PTEN expression

“…UFC1 repressed PTEN expression via the recruitment of EZH2 and the subsequent epigenetic modification. Our results are consistent with those reported by Gan et al showing that EZH2 induces EMT and pluripotency of gastric cancer cells by suppressing PTEN expression 34 .…”

“…The recent studies have shown that EZH2 regulates diverse cellular processes and participates in cancer development, progression and metastasis. Many lncRNAs bind to EZH2 to epigenetically silence gene expression in NSCLC cells [22][23][24][25][26][27][28][29][30][31][32][33][34] , such as TUG1 22 , ANRIL 23 , PANDAR 24 , PVT1 25 , and PCAT6 26 . These lncRNAs interact with EZH2 and regulate the expression of distinct target genes, including p21, KLF2, p57, Bcl2, LATS2, and p57.…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…It was hypothesized that overexpression of the regulator of G-protein signaling pathway 1 (RGS1) might promote the transition of stem cells into CSCs [308]. Besides, CSCs are involved in EMT progression via a vast number of mechanisms, including an overactivation of KRAS, STAT3, Rac1, Wnt, Notch, PTEN, ERK, NF-κB signaling pathways, or hypoxic microenvironment [309][310][311][312][313][314][315][316][317][318]. Recently, researchers have proposed the role of CSC-associated protein, leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2), in gastric cancer and EMT initiation [319].…”

PCAT‐1 contributes to cisplatin resistance in gastric cancer through epigenetically silencing PTEN via recruiting EZH2

“…15,16 Moreover, PTEN could be suppressed by EZH2 through the enrichment of H3K27me3 on its promoter region in various cancers. 17,18 Thus, we wondered whether PCAT-1 epigenetically repressed PTEN through EZH2 in GC. First, starBase analysis demonstrated that PCAT-1 was positively correlated with EZH2 level in STAD tissues (n = 375) from TCGA ( Figure 3A).…”