The polycomb group protein EZH2 induces epithelial\u2013mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter

Lu Gan,Jieyun Zhang,Cong Tan,Zhenhua Wu,Ruixi Hua,Weiwei Weng,Weiqi Sheng,Weijian Guo,Yiwei Gong,Midie Xu

doi:10.1186/s13045-017-0547-3

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.

Highlights

The influences of oncogenic enhancer of zeste homolog 2 (Ezh2) on the progression and prognosis of gastric cancer (GC) and the underlying mechanisms are still poorly understood
The positive expression of Ezh2 protein was observed in 72 (68.6%) cases (Fig. 1c). These findings strongly indicated that Ezh2 is overexpressed in GC
We found that the Akt phosphorylation and PTEN expression varied with Ezh2 expression, PTEN was significantly decreased while phosphorylated Akt was significantly elevated in Ezh2-overexpressing cells, whereas both expressions were reversed in Ezh2-knockdown cells (Fig. 4a)

Summary

Introduction

The influences of oncogenic Ezh on the progression and prognosis of gastric cancer (GC) and the underlying mechanisms are still poorly understood. A panel of genes including HOTAIR [17], CCAT2 [18], and TP53 [19] that implicated in the EMT or pluripotent phenotype have been reported to be acting as the upstream moleculars of Ezh dysregulation in GC. These findings raised the question that what the downstream of functional Ezh is in cancer EMT phenotype and sphere-forming capacity, resulting in the carcinogenesis and progression of GC

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Results

Conclusion