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Exp. Mol. Med., 25 March 2024 | https://doi.org/10.1038/s12276-024-01185-3 Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism

Kyung Hee Jung ^1,5,*, Sujin Lee ^2,5, Han Sun Kim ^2,5, Jin-Mo Kim ^2,5, Yun Ji Lee ¹, Min Seok Park ¹, Myeong-Seong Seo ¹, Misu Lee ³, Mijin Yun^4,*, Sunghyouk Park ^2,* and Soon-Sun Hong ^1,*

¹Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea.
²Department of Manufacturing Pharmacy, Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
³Division of Life Science, College of Life Science and Bioengineering, Incheon National University, Incheon 21999, Korea.
⁴Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 03722, Korea.
⁵These authors contributed equally: Kyung Hee Jung, Sujin Lee, Han Sun Kim, Jin-Mo Kim.

^*Corresponding authors: correspondence to Kyung Hee Jung, Mijin Yun, Sunghyouk Park or Soon-Sun Hong

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.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-26)
연구진국내 연구진
분야 생명과학 > 생화학

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