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Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers
- Chatterjee, Nilanjana;
- Pazarentzos, Evangelos;
- Mayekar, Manasi K;
- Gui, Philippe;
- Allegakoen, David V;
- Hrustanovic, Gorjan;
- Olivas, Victor;
- Lin, Luping;
- Verschueren, Erik;
- Johnson, Jeffrey R;
- Hofree, Matan;
- Yan, Jenny J;
- Newton, Billy W;
- Dollen, John V;
- Earnshaw, Charles H;
- Flanagan, Jennifer;
- Chan, Elton;
- Asthana, Saurabh;
- Ideker, Trey;
- Wu, Wei;
- Suzuki, Junji;
- Barad, Benjamin A;
- Kirichok, Yuriy;
- Fraser, James S;
- Weiss, William A;
- Krogan, Nevan J;
- Tulpule, Asmin;
- Sabnis, Amit J;
- Bivona, Trever G
- et al.
Published Web Location
https://doi.org/10.1016/j.celrep.2019.07.063Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.
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