Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer.

Jilong Hu,Zhinan Zheng,Yuxin Cao,Jia Lei,Zhi Zheng,Chuanjun Chen,Qiyun Li,Stéphane Mandard

doi:10.1155/2021/5589342

Abstract

Enhancer of zeste homolog 2 (EZH2) is abnormally highly expressed in pancreatic cancer (PC). However, it is not ideal to treat PC by inhibiting EZH2. This study reported that the combined use of pan-peroxisome proliferator-activated receptor (PPAR) agonist could significantly improve the anti-PC effect of EZH2 inhibitor. In vitro, PC cell lines PANC-1 and AsPC-1 were cultured, and MTT and flow cytometry were performed to observe the effects of pan-PPAR agonist bezafibrate and EZH2 selective inhibitor GSK126 on cell viability and apoptosis. In vivo, CDXs of PANC-1 and AsPC-1 were established to observe the effects of bezafibrate and GSK126 on bearing tumors. Western blotting was performed to detect the protein expressions of H3K27me3, β-catenin, p-β-catenin, cyclin D1, c-Myc, and cleaved caspase 3 in vitro and in vivo. The results showed that bezafibrate significantly improved the effects of GSK126 on proliferation inhibition and apoptosis promotion in vitro and the growth suppression of CDX tumors in vivo. It also significantly enhanced the effects of GSK126 on upregulating the expression level of p-β-catenin and that of cleaved caspase 3 in vitro and in vivo. In parallel, downregulation of the expression levels of H3K27me3, β-catenin, cyclin D1, and c-Myc was also observed in vitro or in vivo. These results suggest that the combination of bezafibrate and GSK126 has synergistic effects on PC, and the molecular mechanism may be related to the enhanced inhibition of the Wnt/β-catenin signaling pathway. We believe that targeting the EZH2-PPAR axis is a potential therapeutic pathway for PC.

Highlights

The incidence of pancreatic cancer (PC) ranks 14th in the world, and it has become the 7th leading cause of cancer death in the world due to its extremely high degree of malignancy [1]
We found that the anti-PC effect of Enhancer of zeste homolog 2 (EZH2) inhibitor GSK126 can be significantly improved by combining bezafibrate, an agonist of pan-peroxisome proliferator-activated receptors (PPAR)
The Quantitative Polymerase Chain Reaction (qPCR) was used to detect the mRNA transcription level of EZH2, and the result showed that the relative mRNA levels of EZH2 were significantly upregulated in PANC-1 and AsPC-1 (Figure 1(e)), which is consistent with the results of western blotting

Summary

Introduction

The incidence of pancreatic cancer (PC) ranks 14th in the world, and it has become the 7th leading cause of cancer death in the world due to its extremely high degree of malignancy [1]. The incidence of PC in China has been increasing year by year, and it ranked the 6th cause of cancer death in the country in 2015 [2]. PC has a short course of disease and rapid development. It is difficult to treat in the late stage, which makes high clinical mortality rate of PC [3]. Surgical resection is the only effective method for patients with PC to obtain a cure and long-term survival, while most patients with PC lose the opportunity for surgery due to the late disease stage [4]. The molecular mechanism of PC is still unclear, which limits the drug development and precise treatment of PC [4, 5]

Methods

Results

Conclusion