Altered metabolism represents a fundamental difference between cancer and normal cells. Accordingly, targeting metabolic pathways holds great promise for improved cancer therapy. Our recent work (Cell Reports, 2017) uncovered that Phosphoglycerate Dehydrogenase (PHGDH), the rate-limiting enzyme in serine biosynthesis, is highly expressed in an adenocarcinoma subset with poor prognosis. We found that JosD2 deubiquitinase regulates the stability of PHGDH and it remains the only known target for JosD2. Yet, it is very likely that JosD2 controls the stability of additional target proteins involved in metabolism. To this end, our Goal is to globally identify the targets of JosD2 and to study its potential effects on metabolism and tumor growth pathways. Our prel. data suggests that JosD2 regulates the protein stability and enzymatic activity of key enzymes in glycolysis. This inhibits the production of amino acids, lactate (end-product of glycolysis) and ATP. This provides a strong rationale to investigate the molecular mechanisms on how JosD2 regulates cancer cell metabolism and we outline a comprehensive integrative research plan to biochemically characterize this and to test the targetability of JosD2 and its metabolic targets. We employ metabolomics, quantitative proteomics, biochemical and genetic approaches. The studies proposed here will define how JosD2 control metabolism in cancer cells and in tumors with the ultimate aim to uncover new therapeutic avenues that may lay a foundation on how to successfully target metabolism in patients.

References/Background Reading:
1. 12. Zhang B, Zheng A, Hydbring P, Ambroise G, Ouchida A, Goiny, M, Vakifahmetoglu-Norberg H, Norberg E (2017) PHGDH Defines a Metabolic Subtype in Lung Adenocarcinomas with Poor Prognosis. Cell Reports 2017 Jun 13;19(11):2289-2303.

2. Lima Queiroz A, Vakifahmetoglu-Norberg H, Norberg E. Resistant to Targeted Therapies – Aim for Metabolic Liabilities. Theranostics. 2018 Jan 2;12(1):1-222

3. 5. Caro P*, Kishan AU*, Norberg E*, Stanley IA, Chapuy B, et al. (2012) Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22: 547-560. *equal contribution

4. 1. Stanley IA, Ribeiro SM, Gimenez-Cassina A, Norberg E, Danial NN (2014) Changing appetites: the adaptive advantages of fuel choice. Trends Cell Biol 24: 118-127.