Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axis
Abstract Lipid metabolism is implicated in the initiation and progression of human colorectal cancer (CRC). Carbonyl reductase 4 (CBR4), a member of the carbonyl reductase family, plays a role in the biosynthesis of fatty acids. However, its involvement in CRC remains poorly understood. In this stud...
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BMC
2025-04-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-025-03776-0 |
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| author | Jingjing Zhang Tiaotiao Chen Wencheng Wu Chunhua Hu Bangting Wang Xiaofeng Jia Mujie Ye |
| author_facet | Jingjing Zhang Tiaotiao Chen Wencheng Wu Chunhua Hu Bangting Wang Xiaofeng Jia Mujie Ye |
| author_sort | Jingjing Zhang |
| collection | DOAJ |
| description | Abstract Lipid metabolism is implicated in the initiation and progression of human colorectal cancer (CRC). Carbonyl reductase 4 (CBR4), a member of the carbonyl reductase family, plays a role in the biosynthesis of fatty acids. However, its involvement in CRC remains poorly understood. In this study, we aim to explore the function of CBR4 in CRC. Our findings indicated that the expression of CBR4 was significantly reduced in CRC tissues. Functional analyses revealed that CBR4 functions to inhibit cell proliferation, colony formation, migration, invasion, and tumor growth in vivo. Mechanistically, CBR4 interacts with fatty acid synthase (FASN), activating the ubiquitin-proteasome pathway, which leads to a reduction in FASN expression, thereby inhibiting the mTOR pathway and curtailing CRC development. Orlistat, a known FASN inhibitor, demonstrated anti-cancer properties both in vitro and in vivo. Additionally, DNMT3B, a DNA methyltransferase, contributed to the down-regulation of CBR4 by inducing methylation in the promoter region. In summary, our findings suggest that the DNMT3B/CBR4/FASN/mTOR signaling pathway is crucial in the advancement of CRC, and elucidate the potential mechanism by which enzymatic carbonyl reduction and lipid metabolism may be connected to CRC progression, offering a novel therapeutic strategy for its clinical management. |
| format | Article |
| id | doaj-art-8579056ed2f74c06a7fa36c2dfa35ae5 |
| institution | OA Journals |
| issn | 1475-2867 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-8579056ed2f74c06a7fa36c2dfa35ae52025-08-20T02:27:06ZengBMCCancer Cell International1475-28672025-04-0125111310.1186/s12935-025-03776-0Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axisJingjing Zhang0Tiaotiao Chen1Wencheng Wu2Chunhua Hu3Bangting Wang4Xiaofeng Jia5Mujie Ye6Department of Medical Image, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineDepartment of Geriatrics, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical UniversityDepartment of Pathology, Changzhou First People’s Hospital, The Third Affiliated Hospital of Suzhou UniversityNeuroendocrine Tumor Diagnosis and Treatment Center of Jiangsu Province Hospital, The First Affiliated Hospital with Nanjing Medical University; Neuroendocrine Tumor Diagnosis and Treatment Center of Jiangsu Province; Institute of Neuroendocrine Tumor of Collaborative Innovation Center for Cancer Personalized Medicine of Jiangsu Province; Institute of Neuroendocrine Tumor of Nanjing Medical UniversityDepartment of Gastroenterology, The First Affiliated Hospital with Nanjing Medical UniversityDepartment of Medical Image, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNeuroendocrine Tumor Diagnosis and Treatment Center of Jiangsu Province Hospital, The First Affiliated Hospital with Nanjing Medical University; Neuroendocrine Tumor Diagnosis and Treatment Center of Jiangsu Province; Institute of Neuroendocrine Tumor of Collaborative Innovation Center for Cancer Personalized Medicine of Jiangsu Province; Institute of Neuroendocrine Tumor of Nanjing Medical UniversityAbstract Lipid metabolism is implicated in the initiation and progression of human colorectal cancer (CRC). Carbonyl reductase 4 (CBR4), a member of the carbonyl reductase family, plays a role in the biosynthesis of fatty acids. However, its involvement in CRC remains poorly understood. In this study, we aim to explore the function of CBR4 in CRC. Our findings indicated that the expression of CBR4 was significantly reduced in CRC tissues. Functional analyses revealed that CBR4 functions to inhibit cell proliferation, colony formation, migration, invasion, and tumor growth in vivo. Mechanistically, CBR4 interacts with fatty acid synthase (FASN), activating the ubiquitin-proteasome pathway, which leads to a reduction in FASN expression, thereby inhibiting the mTOR pathway and curtailing CRC development. Orlistat, a known FASN inhibitor, demonstrated anti-cancer properties both in vitro and in vivo. Additionally, DNMT3B, a DNA methyltransferase, contributed to the down-regulation of CBR4 by inducing methylation in the promoter region. In summary, our findings suggest that the DNMT3B/CBR4/FASN/mTOR signaling pathway is crucial in the advancement of CRC, and elucidate the potential mechanism by which enzymatic carbonyl reduction and lipid metabolism may be connected to CRC progression, offering a novel therapeutic strategy for its clinical management.https://doi.org/10.1186/s12935-025-03776-0Colorectal cancerCBR4FASNDNA methylationmTOR |
| spellingShingle | Jingjing Zhang Tiaotiao Chen Wencheng Wu Chunhua Hu Bangting Wang Xiaofeng Jia Mujie Ye Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axis Cancer Cell International Colorectal cancer CBR4 FASN DNA methylation mTOR |
| title | Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axis |
| title_full | Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axis |
| title_fullStr | Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axis |
| title_full_unstemmed | Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axis |
| title_short | Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axis |
| title_sort | carbonyl reductase 4 suppresses colorectal cancer progression through the dnmt3b cbr4 fasn mtor axis |
| topic | Colorectal cancer CBR4 FASN DNA methylation mTOR |
| url | https://doi.org/10.1186/s12935-025-03776-0 |
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