Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism
Abstract Acetyl-CoA synthetase 2 (ACSS2)-dependent acetate usage has generally been associated with tumorigenesis and increased malignancy in cancers under nutrient-depleted conditions. However, the nutrient usage and metabolic characteristics of the liver differ from those of other organs; therefor...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-03-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01185-3 |
| _version_ | 1797219990031564800 |
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| author | Kyung Hee Jung Sujin Lee Han Sun Kim Jin-Mo Kim Yun Ji Lee Min Seok Park Myeong-Seong Seo Misu Lee Mijin Yun Sunghyouk Park Soon-Sun Hong |
| author_facet | Kyung Hee Jung Sujin Lee Han Sun Kim Jin-Mo Kim Yun Ji Lee Min Seok Park Myeong-Seong Seo Misu Lee Mijin Yun Sunghyouk Park Soon-Sun Hong |
| author_sort | Kyung Hee Jung |
| collection | DOAJ |
| description | Abstract Acetyl-CoA synthetase 2 (ACSS2)-dependent acetate usage has generally been associated with tumorigenesis and increased malignancy in cancers under nutrient-depleted conditions. However, the nutrient usage and metabolic characteristics of the liver differ from those of other organs; therefore, the mechanism of ACSS2-mediated acetate metabolism may also differ in liver cancer. To elucidate the underlying mechanisms of ACSS2 in liver cancer and acetate metabolism, the relationships between patient acetate uptake and metabolic characteristics and between ACSS2 and tumor malignancies were comprehensively studied in vitro, in vivo and in humans. Clinically, we initially found that ACSS2 expression was decreased in liver cancer patients. Moreover, PET-CT imaging confirmed that lower-grade cancer cells take up more 11C-acetate but less 18F-fluorodeoxyglucose (18F-FDG); however, this trend was reversed in higher-grade cancer. Among liver cancer cells, those with high ACSS2 expression avidly absorbed acetate even in a glucose-sufficient environment, whereas those with low ACSS2 expression did not, thereby showing correlations with their respective ACSS2 expression. Metabolomic isotope tracing in vitro and in vivo revealed greater acetate incorporation, greater lipid anabolic metabolism, and less malignancy in high-ACSS2 tumors. Notably, ACSS2 downregulation in liver cancer cells was associated with increased tumor occurrence in vivo. In human patient cohorts, patients in the low-ACSS2 subgroup exhibited reduced anabolism, increased glycolysis/hypoxia, and poorer prognosis. We demonstrated that acetate uptake by ACSS2 in liver cancer is independent of glucose depletion and contributes to lipid anabolic metabolism and reduced malignancy, thereby leading to a better prognosis for liver cancer patients. |
| first_indexed | 2024-04-24T12:42:25Z |
| format | Article |
| id | doaj.art-3893a9536dae4894a412178b25903b59 |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-04-24T12:42:25Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-3893a9536dae4894a412178b25903b592024-04-07T11:09:39ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132024-03-0156372173310.1038/s12276-024-01185-3Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolismKyung Hee Jung0Sujin Lee1Han Sun Kim2Jin-Mo Kim3Yun Ji Lee4Min Seok Park5Myeong-Seong Seo6Misu Lee7Mijin Yun8Sunghyouk Park9Soon-Sun Hong10Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha UniversityDepartment of Manufacturing Pharmacy, Natural Products Research Institute, College of Pharmacy, Seoul National UniversityDepartment of Manufacturing Pharmacy, Natural Products Research Institute, College of Pharmacy, Seoul National UniversityDepartment of Manufacturing Pharmacy, Natural Products Research Institute, College of Pharmacy, Seoul National UniversityDepartment of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha UniversityDepartment of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha UniversityDepartment of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha UniversityDivision of Life Science, College of Life Science and Bioengineering, Incheon National UniversityDepartment of Nuclear Medicine, Severance Hospital, Yonsei University College of MedicineDepartment of Manufacturing Pharmacy, Natural Products Research Institute, College of Pharmacy, Seoul National UniversityDepartment of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha UniversityAbstract Acetyl-CoA synthetase 2 (ACSS2)-dependent acetate usage has generally been associated with tumorigenesis and increased malignancy in cancers under nutrient-depleted conditions. However, the nutrient usage and metabolic characteristics of the liver differ from those of other organs; therefore, the mechanism of ACSS2-mediated acetate metabolism may also differ in liver cancer. To elucidate the underlying mechanisms of ACSS2 in liver cancer and acetate metabolism, the relationships between patient acetate uptake and metabolic characteristics and between ACSS2 and tumor malignancies were comprehensively studied in vitro, in vivo and in humans. Clinically, we initially found that ACSS2 expression was decreased in liver cancer patients. Moreover, PET-CT imaging confirmed that lower-grade cancer cells take up more 11C-acetate but less 18F-fluorodeoxyglucose (18F-FDG); however, this trend was reversed in higher-grade cancer. Among liver cancer cells, those with high ACSS2 expression avidly absorbed acetate even in a glucose-sufficient environment, whereas those with low ACSS2 expression did not, thereby showing correlations with their respective ACSS2 expression. Metabolomic isotope tracing in vitro and in vivo revealed greater acetate incorporation, greater lipid anabolic metabolism, and less malignancy in high-ACSS2 tumors. Notably, ACSS2 downregulation in liver cancer cells was associated with increased tumor occurrence in vivo. In human patient cohorts, patients in the low-ACSS2 subgroup exhibited reduced anabolism, increased glycolysis/hypoxia, and poorer prognosis. We demonstrated that acetate uptake by ACSS2 in liver cancer is independent of glucose depletion and contributes to lipid anabolic metabolism and reduced malignancy, thereby leading to a better prognosis for liver cancer patients.https://doi.org/10.1038/s12276-024-01185-3 |
| spellingShingle | Kyung Hee Jung Sujin Lee Han Sun Kim Jin-Mo Kim Yun Ji Lee Min Seok Park Myeong-Seong Seo Misu Lee Mijin Yun Sunghyouk Park Soon-Sun Hong Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism Experimental and Molecular Medicine |
| title | Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism |
| title_full | Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism |
| title_fullStr | Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism |
| title_full_unstemmed | Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism |
| title_short | Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism |
| title_sort | acetyl coa synthetase 2 contributes to a better prognosis for liver cancer by switching acetate glucose metabolism |
| url | https://doi.org/10.1038/s12276-024-01185-3 |
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