Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A
Peroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found t...
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| Format: | Article |
| Language: | English |
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Wiley
2021-01-01
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| Series: | PPAR Research |
| Online Access: | http://dx.doi.org/10.1155/2021/6663782 |
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| _version_ | 1832552880861609984 |
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| author | Rui Kong Nan Wang Wei Han Wen Bao Jie Lu |
| author_facet | Rui Kong Nan Wang Wei Han Wen Bao Jie Lu |
| author_sort | Rui Kong |
| collection | DOAJ |
| description | Peroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found that PPARA was expressed at relatively low levels in pancancers, and Kaplan-Meier analyses revealed that high PPARA protein expression was correlated with better survival of patients with colon cancer. In vitro experiments showed that fenofibrate regulated cell cycle distribution, promoted apoptosis, and suppressed cell proliferation and epithelial mesenchymal transition by activating PPARA. PPARA activation inhibited DNMT1 activity and abolished methylation-mediated CDKN2A repression. Downregulation of cyclin-CDK complexes led to the restoration of CDKN2A, which caused cell cycle arrest in the G1 phase via regulation of the CDKN2A/RB/E2F pathway. Finally, we demonstrated that fenofibrate administration inhibited tumor growth and DNMT1 activity in vivo. The PPARA agonist, fenofibrate, might serve as an applicable agent for epigenetic therapy of colon cancer patients. |
| format | Article |
| id | doaj-art-cf1a8f2429664d86a91cf1fc8b8f02d6 |
| institution | Kabale University |
| issn | 1687-4757 1687-4765 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | PPAR Research |
| spelling | doaj-art-cf1a8f2429664d86a91cf1fc8b8f02d62025-02-03T05:57:35ZengWileyPPAR Research1687-47571687-47652021-01-01202110.1155/2021/66637826663782Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2ARui Kong0Nan Wang1Wei Han2Wen Bao3Jie Lu4Department of Gastroenterology, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, ChinaDepartment of Gastroenterology, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, ChinaDepartment of Gastroenterology, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, ChinaDepartment of Gastroenterology, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, ChinaDepartment of Gastroenterology, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, ChinaPeroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found that PPARA was expressed at relatively low levels in pancancers, and Kaplan-Meier analyses revealed that high PPARA protein expression was correlated with better survival of patients with colon cancer. In vitro experiments showed that fenofibrate regulated cell cycle distribution, promoted apoptosis, and suppressed cell proliferation and epithelial mesenchymal transition by activating PPARA. PPARA activation inhibited DNMT1 activity and abolished methylation-mediated CDKN2A repression. Downregulation of cyclin-CDK complexes led to the restoration of CDKN2A, which caused cell cycle arrest in the G1 phase via regulation of the CDKN2A/RB/E2F pathway. Finally, we demonstrated that fenofibrate administration inhibited tumor growth and DNMT1 activity in vivo. The PPARA agonist, fenofibrate, might serve as an applicable agent for epigenetic therapy of colon cancer patients.http://dx.doi.org/10.1155/2021/6663782 |
| spellingShingle | Rui Kong Nan Wang Wei Han Wen Bao Jie Lu Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A PPAR Research |
| title | Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A |
| title_full | Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A |
| title_fullStr | Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A |
| title_full_unstemmed | Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A |
| title_short | Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A |
| title_sort | fenofibrate exerts antitumor effects in colon cancer via regulation of dnmt1 and cdkn2a |
| url | http://dx.doi.org/10.1155/2021/6663782 |
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