p53-mediated Regulation of Phosphoglycerate Dehydrogenase (PHGDH) is crucial for the Apoptotic Response Upon Serine Starvation [Metabolism]

November 17th, 2014 by Ou, Y., Wang, S.-J., Jiang, L., Zheng, B., Gu, W.

Although p53 is frequently mutated in human cancers, about 80% of human melanomas retain wild-type p53. Here, we report that PHGDH, the key metabolic enzyme that cata-lyzes the rate-limiting step of serine biosynthesis pathway, is a target of p53 in human melanoma cells. p53 suppresses its expression and inhibits de novo serine biosynthesis. Notably, upon serine starvation, p53-mediated cell death is dramatically enhanced in response to Nutlin-3 treatment. Moreover, PHGDH is recently found to be frequently amplified in human melanomas. We found that PHGDH overexpression significantly suppresses the apoptotic response, whereas RNAi-mediated knock-down of endogenous PHGDH promotes apoptosis under the same treatment. These results demonstrate an important role of p53 in regulating serine biosynthesis pathway through suppressing PHGDH expression and reveal serine deprivation as a novel approach to sensitize p53-mediated apoptotic responses in human melanoma cells.