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

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.

Automated summary

The study by Ma et al. reveals that PHGDH translocates from the cytoplasm to the nucleus under glucose restriction via phosphorylation by p38 and AMPK, resulting in altered activity that affects NAD(+) levels and PARP1 activity. This novel nutrient-sensing mechanism involving PHGDH highlights its critical role in tumour growth and cell fate decisions.