EPN1 regulates PHGDH activation and subcellular localization in cancer

The cancer-dependent Metabolic reprogramming is essential for cell proliferation and thus its components can serve as potential targets for anti-tumor drugs. One of the main metabolic pathways that are dysregulated in cancer is serine biosynthesis which is essential also for nucleotide production. The metabolic enzyme phosphoglycerate dehydrogenase (PHGDH) is the first rate-limiting enzyme in this metabolic pathway. Elevation of PHGDH is highly associated with human tumor progression and development. However, the means by which the cancer cells regulate PHGDH activity is still unclear. To identify any potential regulator of PHGDH we subjected this enzyme to LC-MS analyses to systematically identify all its interacting partners. We identified in both the breast cancer cell line, MDA-MB-468 and the non-small cell lung cancer cell line, A549 that PHGDH interacts with Epsin1 (EPN1), a major player in clathrin-mediated endocytosis. Furthermore, we demonstrate that this PHGDH-EPN1 interaction regulates its activity and subcellular localization. Additionally, we show that serine restriction induces this binding and inhibits the PHGDH activity- indicating a feedback loop that corresponds to the cellular metabolic environment. Overall, these results may reveal an unknown mechanism that regulates PHGDH in cancer.