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  3. Ketogenic diet reshapes cancer metabolism through lysine β-hydroxybutyrylation

Ketogenic diet reshapes cancer metabolism through lysine β-hydroxybutyrylation

  • Nat Metab. 2024 Aug;6(8):1505-1528. doi: 10.1038/s42255-024-01093-w.
Junhong Qin # 1,  Xinhe Huang # 2,  Shengsong Gou # 1,  Sitao Zhang # 1,  Yujie Gou 2,  Qian Zhang 1,  Hongyu Chen 1,  Lin Sun 3,  Miaomiao Chen 2,  Dan Liu 2,  Cheng Han 2,  Min Tang 1,  Zihao Feng 2,  Shenghui Niu 1,  Lin Zhao 1,  Yingfeng Tu 1,  Zexian Liu 4,  Weimin Xuan 3,  Lunzhi Dai 5,  Da Jia 6,  Yu Xue 7 8
Affiliations

Affiliations

  • 1 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
  • 2 Key Laboratory of Molecular Biophysics of Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Frontiers Science Center for Synthetic Biology, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, China.
  • 4 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
  • 5 National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China.
  • 6 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China. Jiada@scu.edu.cn.
  • 7 Key Laboratory of Molecular Biophysics of Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. xueyu@hust.edu.cn.
  • 8 Nanjing University Institute of Artificial Intelligence Biomedicine, Nanjing, China. xueyu@hust.edu.cn.
  • # Contributed equally.
PMID: 39134903 DOI: 10.1038/s42255-024-01093-w
Abstract

Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification induced by the ketogenic diet (KD), a diet showing therapeutic effects on multiple human diseases. Little is known how cellular processes are regulated by Kbhb. Here we show that protein Kbhb is strongly affected by the KD through a multi-omics analysis of mouse livers. Using a small training dataset with known functions, we developed a bioinformatics method for the prediction of functionally important lysine modification sites (pFunK), which revealed functionally relevant Kbhb sites on various proteins, including aldolase B (ALDOB) Lys108. KD consumption or β-hydroxybutyrate supplementation in hepatocellular carcinoma cells increases ALDOB Lys108bhb and inhibits the enzymatic activity of ALDOB. A Kbhb-mimicking mutation (p.Lys108Gln) attenuates ALDOB activity and its binding to substrate fructose-1,6-bisphosphate, inhibits mammalian target of rapamycin signalling and glycolysis, and markedly suppresses Cancer cell proliferation. Our study reveals a critical role of Kbhb in regulating Cancer cell metabolism and provides a generally applicable algorithm for predicting functionally important lysine modification sites.

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