Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer
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 eff...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-01-01
|
| Series: | PPAR Research |
| Online Access: | http://dx.doi.org/10.1155/2021/5589342 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832559516013559808 |
|---|---|
| author | Jilong Hu Zhinan Zheng Jia Lei Yuxin Cao Qiyun Li Zhi Zheng Chuanjun Chen |
| author_facet | Jilong Hu Zhinan Zheng Jia Lei Yuxin Cao Qiyun Li Zhi Zheng Chuanjun Chen |
| author_sort | Jilong Hu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d2fb716c111f448caf018986d4aa7de4 |
| institution | Kabale University |
| issn | 1687-4765 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | PPAR Research |
| spelling | doaj-art-d2fb716c111f448caf018986d4aa7de42025-02-03T01:29:53ZengWileyPPAR Research1687-47652021-01-01202110.1155/2021/55893425589342Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic CancerJilong Hu0Zhinan Zheng1Jia Lei2Yuxin Cao3Qiyun Li4Zhi Zheng5Chuanjun Chen6Department of Abdominal Surgery OncologyDepartment of PharmacyHaiyuan CollegeDepartment of MedicineDepartment of Abdominal Surgery OncologyDepartment of Internal Medicine 5th DivisionNanchang Royo Biotech Co.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.http://dx.doi.org/10.1155/2021/5589342 |
| spellingShingle | Jilong Hu Zhinan Zheng Jia Lei Yuxin Cao Qiyun Li Zhi Zheng Chuanjun Chen Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer PPAR Research |
| title | Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer |
| title_full | Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer |
| title_fullStr | Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer |
| title_full_unstemmed | Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer |
| title_short | Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer |
| title_sort | targeting the ezh2 ppar axis is a potential therapeutic pathway for pancreatic cancer |
| url | http://dx.doi.org/10.1155/2021/5589342 |
| work_keys_str_mv | AT jilonghu targetingtheezh2pparaxisisapotentialtherapeuticpathwayforpancreaticcancer AT zhinanzheng targetingtheezh2pparaxisisapotentialtherapeuticpathwayforpancreaticcancer AT jialei targetingtheezh2pparaxisisapotentialtherapeuticpathwayforpancreaticcancer AT yuxincao targetingtheezh2pparaxisisapotentialtherapeuticpathwayforpancreaticcancer AT qiyunli targetingtheezh2pparaxisisapotentialtherapeuticpathwayforpancreaticcancer AT zhizheng targetingtheezh2pparaxisisapotentialtherapeuticpathwayforpancreaticcancer AT chuanjunchen targetingtheezh2pparaxisisapotentialtherapeuticpathwayforpancreaticcancer |