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

Nilanjana Chatterjee*, Evangelos Pazarentzos, Manasi K. Mayekar, Philippe Gui, David V. Allegakoen, Gorjan Hrustanovic, Victor Olivas, Luping Lin, Erik Verschueren, Jeffrey R. Johnson, M. Hofree, Jenny J. Yan, Billy W. Newton, John V. Dollen, Charles H. Earnshaw, Jennifer Flanagan, E. Chan, Saurabh Asthana, Trey Ideker, Wei WuJ. Suzuki, Benjamin A. Barad, Y. Kirichok, James S. Fraser, William A. Weiss, Nevan J. Krogan, A. Tulpule, Amit J. Sabnis, Trever G. Bivona

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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. The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers.

Original languageAmerican English
Pages (from-to)2317-2330.e8
JournalCell Reports
Volume28
Issue number9
DOIs
StatePublished - 27 Aug 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 The Author(s)

Keywords

  • NF-κB
  • NKAP
  • PDHK1
  • PTEN
  • cancer
  • metabolism
  • protein phosphatase
  • signaling
  • synthetic lethality

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