Cell Reports (Aug 2019)
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,
- 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
Affiliations
- Nilanjana Chatterjee
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
- Evangelos Pazarentzos
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Manasi K. Mayekar
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Philippe Gui
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- David V. Allegakoen
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Gorjan Hrustanovic
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Victor Olivas
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Luping Lin
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Erik Verschueren
- J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; QB3, California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA
- Jeffrey R. Johnson
- J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; QB3, California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA
- Matan Hofree
- Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA
- Jenny J. Yan
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Billy W. Newton
- J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; QB3, California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA
- John V. Dollen
- J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; QB3, California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA
- Charles H. Earnshaw
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
- Jennifer Flanagan
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Elton Chan
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Saurabh Asthana
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Trey Ideker
- Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA
- Wei Wu
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Junji Suzuki
- Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA
- Benjamin A. Barad
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Yuriy Kirichok
- Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA
- James S. Fraser
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
- William A. Weiss
- Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
- Nevan J. Krogan
- J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; QB3, California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA
- Asmin Tulpule
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Amit J. Sabnis
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Trever G. Bivona
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; QB3, California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA; Corresponding author
- Journal volume & issue
-
Vol. 28,
no. 9
pp. 2317 – 2330.e8
Abstract
Summary: 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. Keywords: PTEN, protein phosphatase, PDHK1, NKAP, NF-κB, synthetic lethality, metabolism, signaling, cancer
