p53 Protein-mediated Regulation of Phosphoglycerate Dehydrogenase (PHGDH) Is Crucial for the Apoptotic Response upon Serine Starvation

Background:PHGDH encodes a key metabolic enzyme in the serine biosynthesis pathway and is frequently amplified in melanomas. Results: p53 transcriptionally represses PHGDH expression. Serine starvation promotes p53-mediated apoptosis in melanomas through PHGDH suppression. Conclusion: p53-mediated repression of PHGDH enhances the apoptotic response upon serine starvation in melanoma cells. Significance: The combination of the drugs activating p53 and serine deprivation could be a better treatment for melanomas. 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 catalyzes the rate-limiting step of the serine biosynthesis pathway, is a target of p53 in human melanoma cells. p53 suppresses PHGDH expression and inhibits de novo serine biosynthesis. Notably, upon serine starvation, p53-mediated cell death is enhanced dramatically in response to Nutlin-3 treatment. Moreover, PHGDH has been found recently to be amplified frequently in human melanomas. We found that PHGDH overexpression significantly suppresses the apoptotic response, whereas RNAi-mediated knockdown of endogenous PHGDH promotes apoptosis under the same treatment. These results demonstrate an important role of p53 in regulating the 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.