文献类型：期刊文献

英文题名：The alternative activity of nuclear PHGDH contributes to tumour growth under nutrient stress

作者：Ma, Chunmin[1,2,3];Zheng, Ke[1,2];Jiang, Kun[4,5];Zhao, Qin[1,2];Sha, Nannan[1,2];Wang, Wang[1,2];Yan, Man[1,2];Chen, Tao[6];Zhao, Yuzheng[4,5];Jiang, Yuhui[1,2]

机构：[1]Shanghai Jiao Tong Univ, Sch Med, Dept Liver Surg, Shanghai, Peoples R China;[2]Shanghai Jiao Tong Univ, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes, Renji Hosp,Shanghai Key Lab Pancreat Dis,Sch Med, Shanghai, Peoples R China;[3]Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Sch Med, Dept Rehabil, Shanghai, Peoples R China;[4]East China Univ Sci & Technol, Sch Pharm, Optogenet & Synthet Biol Interdisciplinary Res Ct, State Key Lab Bioreactor Engn,Shanghai Key Lab Ne, Shanghai, Peoples R China;[5]Chinese Acad Med Sci, Res Unit New Tech Live Cell Metab Imaging, Beijing, Peoples R China;[6]Tongji Univ, Shanghai East Hosp, Endoscopy Ctr, Sch Med,Dept Gastroenterol, Shanghai, Peoples R China

年份：2021

卷号：3

期号：10

起止页码：1357

外文期刊名：NATURE METABOLISM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000708364000001)】；

基金：We thank L. -J. Liao at East China Normal University for the technical assistance. This work was supported by National Key R&D Program of China (2020YFA0803602 and 2017YFA0506200 to Y.J.; 2019YFA0904800 to Y.Z.), National Nature Science Foundation of China (81972586 and 81773006 to Y.J.; 32030065, 31722033 and 92049304 to Y.Z.), Shanghai Municipal Education Commission (Gaofeng Clinical Medicine grant 20161319 to Y.J.; Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism grant 2021 Sci & Tech 03-28 to Y.Z.), Research Unit of New Techniques for Live-cell Metabolic Imaging (Chinese Academy of Medical Sciences, 2019-I2M-5-013 to Y.Z.), Innovative research team of high-level local universities in Shanghai, the State Key Laboratory of Bioreactor Engineering and the Fundamental Research Funds for the Central Universities.

语种：英文

摘要：Ma et al. find that PHGDH, which catalyses serine metabolism in the cytoplasm, transits to the nucleus during nutrient stress, where it promotes cell growth and tumorigenesis. 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.