The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response
Abstract Emerging evidence demonstrates that the metabolic and non-metabolic functions of metabolic enzymes play a key role in tumorigenesis and progression. 6-phosphogluconate dehydrogenase (6PGD) is a key metabolic enzyme in the pentose phosphate pathway (PPP), which displays aberrant expressions...
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| Format: | Article |
| Language: | English |
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BMC
2025-07-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03450-3 |
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| author | Mingming Sun Qi Yan Xinru Zhai Xintong Dai Chenxin Yang Huifang Zhao Sizhen Lai Jiyan Wang Lian Li Zhen Li Yanping Li Taoyuan Wang Tao He Jun Xue Zhenghu Jia Chunze Zhang Shuai Zhang Changliang Shan |
| author_facet | Mingming Sun Qi Yan Xinru Zhai Xintong Dai Chenxin Yang Huifang Zhao Sizhen Lai Jiyan Wang Lian Li Zhen Li Yanping Li Taoyuan Wang Tao He Jun Xue Zhenghu Jia Chunze Zhang Shuai Zhang Changliang Shan |
| author_sort | Mingming Sun |
| collection | DOAJ |
| description | Abstract Emerging evidence demonstrates that the metabolic and non-metabolic functions of metabolic enzymes play a key role in tumorigenesis and progression. 6-phosphogluconate dehydrogenase (6PGD) is a key metabolic enzyme in the pentose phosphate pathway (PPP), which displays aberrant expressions and functions in cancer. However, whether 6PGD serves non-metabolic functions in regulating cancer progression and drug response has not been reported. Here, we found that highly expressed 6PGD contributes to colorectal cancer (CRC) tumor growth and tumor metastasis. Mechanistically, 6PGD binds to ALKBH5 and inhibits its activity through the non-metabolic activity of 6PGD; this increases m6A modification levels and the stability of MDM2 mRNA and decreases the p53 protein stability, subsequently activating the expression of CCNA2 and HMGA2, which are responses to CRC tumor growth and tumor metastasis. Collectively, these findings reveal the multi-functionality of 6PGD in promoting CRC tumor growth, tumor metastasis, and drug responses through its non-metabolic activity. |
| format | Article |
| id | doaj-art-848b6860cd264ef8b0416ec3bc4d7419 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-848b6860cd264ef8b0416ec3bc4d74192025-08-20T03:45:39ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-07-0144112010.1186/s13046-025-03450-3The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug responseMingming Sun0Qi Yan1Xinru Zhai2Xintong Dai3Chenxin Yang4Huifang Zhao5Sizhen Lai6Jiyan Wang7Lian Li8Zhen Li9Yanping Li10Taoyuan Wang11Tao He12Jun Xue13Zhenghu Jia14Chunze Zhang15Shuai Zhang16Changliang Shan17State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversitySchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai UniversityKingMed School of Laboratory Medicine, Guangzhou Medical UniversityDepartment of Pathology, Institute of Precision Medicine, Jining Medical UniversityCardiothoracic Surgery Department, Characteristic Medical Center of the Chinese People’s Armed Police ForceDepartment of Pathology, Characteristic Medical Center of The Chinese People’s Armed Police ForceDepartment of General Surgery, The First Affiliated Hospital of Hebei North UniversityThe First Affiliated Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan UniversityDepartment of Colorectal Surgery, Tianjin Union Medical Center, Nankai UniversitySchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityAbstract Emerging evidence demonstrates that the metabolic and non-metabolic functions of metabolic enzymes play a key role in tumorigenesis and progression. 6-phosphogluconate dehydrogenase (6PGD) is a key metabolic enzyme in the pentose phosphate pathway (PPP), which displays aberrant expressions and functions in cancer. However, whether 6PGD serves non-metabolic functions in regulating cancer progression and drug response has not been reported. Here, we found that highly expressed 6PGD contributes to colorectal cancer (CRC) tumor growth and tumor metastasis. Mechanistically, 6PGD binds to ALKBH5 and inhibits its activity through the non-metabolic activity of 6PGD; this increases m6A modification levels and the stability of MDM2 mRNA and decreases the p53 protein stability, subsequently activating the expression of CCNA2 and HMGA2, which are responses to CRC tumor growth and tumor metastasis. Collectively, these findings reveal the multi-functionality of 6PGD in promoting CRC tumor growth, tumor metastasis, and drug responses through its non-metabolic activity.https://doi.org/10.1186/s13046-025-03450-3Colorectal cancer (CRC)6-phosphogluconate dehydrogenase (6PGD)Non-metabolic activityProliferationMetastasis |
| spellingShingle | Mingming Sun Qi Yan Xinru Zhai Xintong Dai Chenxin Yang Huifang Zhao Sizhen Lai Jiyan Wang Lian Li Zhen Li Yanping Li Taoyuan Wang Tao He Jun Xue Zhenghu Jia Chunze Zhang Shuai Zhang Changliang Shan The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response Journal of Experimental & Clinical Cancer Research Colorectal cancer (CRC) 6-phosphogluconate dehydrogenase (6PGD) Non-metabolic activity Proliferation Metastasis |
| title | The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response |
| title_full | The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response |
| title_fullStr | The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response |
| title_full_unstemmed | The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response |
| title_short | The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response |
| title_sort | non metabolic function of 6pgd coordinates ccna2 and hmga2 expression to drive colorectal cancer progression and drug response |
| topic | Colorectal cancer (CRC) 6-phosphogluconate dehydrogenase (6PGD) Non-metabolic activity Proliferation Metastasis |
| url | https://doi.org/10.1186/s13046-025-03450-3 |
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