2. Academic Validation
  3. The alternative activity of nuclear PHGDH contributes to tumour growth under nutrient stress

The alternative activity of nuclear PHGDH contributes to tumour growth under nutrient stress

  • Nat Metab. 2021 Oct;3(10):1357-1371. doi: 10.1038/s42255-021-00456-x.
Chunmin Ma  # 1 2,  Ke Zheng  # 1,  Kun Jiang  # 3 4,  Qin Zhao 1,  Nannan Sha 1,  Wang Wang 1,  Man Yan 1,  Tao Chen 5,  Yuzheng Zhao 6 7,  Yuhui Jiang 8
Affiliations

Affiliations

  • 1 Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Key Laboratory of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Rehabilitation, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
  • 3 Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • 4 Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, China.
  • 5 Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 6 Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China. [email protected].
  • 7 Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, China. [email protected].
  • 8 Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Key Laboratory of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 34663976 DOI: 10.1038/s42255-021-00456-x
Abstract

The multifunctional roles of metabolic enzymes allow for the integration of multiple signals to precisely transduce external stimuli into cell fate decisions. Elevation of 3-phosphoglycerate dehydrogenase (PHGDH), the rate-limiting Enzyme for de novo serine biosynthesis, is broadly associated with human Cancer development; although how PHGDH activity is regulated and its implication in tumorigenesis remains unclear. Here we show that glucose restriction induces the phosphorylation of PHGDH by p38 at Ser371, which promotes the translocation of PHGDH from the cytosol into the nucleus. Concurrently, AMPK phosphorylates PHGDH-Ser55, selectively increasing PHGDH oxidation of malate into oxaloacetate, thus generating NADH. In the nucleus, the altered PHGDH activity restricts NAD+ level and compartmentally repressed NAD+-dependent PARP1 activity for poly(ADP-ribosyl)ation of c-Jun, thereby leading to impaired c-Jun transcriptional activity linked to cell growth inhibition. Physiologically, nuclear PHGDH sustains tumour growth under nutrient stress, and the levels of PHGDH-Ser371 and PHGDH-Ser55 phosphorylation correlate with p38 and AMPK activity, respectively, in clinical human pancreatic Cancer specimens. These findings illustrate a previously unidentified nutrient-sensing mechanism with the critical involvement of a non-canonical metabolic effect of PHGDH and underscore the functional importance of alternative PHGDH activity in tumorigenesis.

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