Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers

• DOI: 10.1016/j.celrep.2019.07.063
• Publication Date: 2019-08-27T14:31:42Z
• Authors: Nilanjana Chatterjee; Evangelos Pazaren...; Manasi K. Mayekar; Philippe Gui; David V. Allegakoen; Gorjan Hrustanovic; Victor Olivas; Luping Lin; Erik Verschueren; Jeffrey R. Johnson; Matan Hofree; Jenny J. Yan; Billy W. Newton; John V. Dollen; Charles H. Earnshaw; Jennifer Flanagan; Elton Chan; Saurabh Asthana; Trey Ideker; Wei Wu; Junji Suzuki; Benjamin A. Barad; Yuriy Kirichok; James S. Fraser; William A. Weiss; Nevan J. Krogan; Asmin Tulpule; Amit J. Sabnis; Trever G. Bivona
• Keywords: Male; PTEN; NKAP; PDHK1; QH301-705.5; Medical Physiology; 610; Mice, SCID; SCID; NF-κB; Cell Line; Mice; 03 medical and health sciences; Mice, Inbred NOD; Cell Line, Tumor; Neoplasms; 616; Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase; Genetics; 2.1 Biological and endogenous factors; cancer; Animals; Humans; Biology (General); Cancer; 0303 health sciences; Tumor; protein phosphatase; NF-kappa B; PTEN Phosphohydrolase; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Biological Sciences; synthetic lethality; 3. Good health; Repressor Proteins; Biological sciences; HEK293 Cells; Inbred NOD; Female; Biochemistry and Cell Biology; signaling; metabolism; Glycolysis

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.