Succinylation of tumor suppressor PPP2R1A K541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling to display oncogene function.
10.1016/j.apsb.2025.07.040
- Author:
Guang YANG
1
;
Yufei WANG
1
;
Hongfeng YUAN
1
;
Huihui ZHANG
1
;
Lina ZHAO
1
;
Chunyu HOU
1
;
Pan LV
1
;
Jihui HAO
2
;
Xiaodong ZHANG
1
Author Information
1. National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin 300060, China.
2. National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
- Publication Type:Journal Article
- Keywords:
Gluconeogenesis;
HAT1;
Lipogenesis;
Liver cancer;
Metabolic remodeling;
PCK1 phosphorylation;
PPP2R1A;
SREBP1;
Succinylation
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5294-5311
- CountryChina
- Language:English
-
Abstract:
Metabolic reprogramming plays a central role in tumors. However, the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood. Here, we try to identify the mechanism by which histone acetyltransferase 1 (HAT1) confers reprogramming of gluconeogenesis/lipogenesis in liver cancer. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice. Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver. Protein phosphatase 2 scaffold subunit alpha (PPP2R1A) promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1 (PCK1) serine 90 dephosphorylation to suppress the tumor growth. HAT1 succinylated PPP2R1A at lysine 541 (K541) to block the assembly of protein phosphatase 2A (PP2A) holoenzyme and interaction with PCK1, resulting in the depression of dephosphorylation of PCK1. HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation, leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1 (SREBP1) nuclear accumulation-induced lipogenesis gene expression, which enhanced the tumor growth. In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.
