Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate

  • Cell Res. 2023 Sep 19. doi: 10.1038/s41422-023-00874-4.
Yu-Qing Wu  #  1 ,  Chen-Song Zhang  #  1 ,  Jinye Xiong  1 ,  Dong-Qi Cai  1 ,  Chen-Zhe Wang  1 ,  Yu Wang  1 ,  Yan-Hui Liu  1 ,  Yu Wang  2 ,  Yiming Li  2 ,  Jian Wu  2 ,  Jianfeng Wu  3 ,  Bin Lan  4 ,  Xuefeng Wang  4 ,  Siwei Chen  1 ,  Xianglei Cao  1 ,  Xiaoyan Wei  1 ,  Hui-Hui Hu  1 ,  Huiling Guo  1 ,  Yaxin Yu  1 ,  Abdul Ghafoor  1 ,  Changchuan Xie  1 ,  Yaying Wu  1 ,  Zheni Xu  1 ,  Cixiong Zhang  1 ,  Mingxia Zhu  1 ,  Xi Huang  1 ,  Xiufeng Sun  1 ,  Shu-Yong Lin  1 ,  Hai-Long Piao  5 ,  Jianyin Zhou  2 ,  Sheng-Cai Lin  6
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 2. Department of Hepatobiliary and Pancreatic Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, China.
  • 3. Laboratory Animal Research Center, Xiamen University, Xiamen, Fujian, China.
  • 4. Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Xiamen, Fujian, China.
  • 5. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China.
  • 6. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • # Contributed equally.
PMID: 37726403 DOI: 10.1038/s41422-023-00874-4
Abstract

Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond Energy Metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote Apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and Apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces Apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents Apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.

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