PHGDH Defines a Metabolic Subtype in Lung Adenocarcinomas with Poor Prognosis

Publication date: 13 June 2017
Source:Cell Reports, Volume 19, Issue 11
Author(s): Boxi Zhang, Adi Zheng, Per Hydbring, Gorbatchev Ambroise, Amanda Tomie Ouchida, Michel Goiny, Helin Vakifahmetoglu-Norberg, Erik Norberg
Molecular signatures are emerging determinants of choice of therapy for lung adenocarcinomas. An evolving therapeutic approach includes targeting metabolic dependencies in cancers. Here, using an integrative approach, we have dissected the metabolic fingerprints of lung adenocarcinomas, and we show that Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine biosynthesis, is highly expressed in a adenocarcinoma subset with poor prognosis. This subset harbors a gene signature for DNA replication and proliferation. Accordingly, models with high levels of PHGDH display rapid proliferation, migration, and selective channeling of serine-derived carbons to glutathione and pyrimidines, while depletion of PHGDH shows potent and selective toxicity to this subset. Differential PHGDH protein levels were defined by its degradation, and the deubiquitinating enzyme JOSD2 is a regulator of its protein stability. Our study provides evidence that a unique metabolic program is activated in a lung adenocarcinoma subset, described by PHGDH, which confers growth and survival and may have therapeutic implications.

Graphical abstract

Teaser

Zhang et al. find that the Phosphoglycerate dehydrogenase (PHGDH) defines a metabolic subtype in lung adenocarcinomas with unique metabolic dependencies. In particular, a flux through the glycolytic pathway feeds the serine-glycine-nucleotide axis required for survival of the rapidly proliferating PHGDH-high subtype.


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