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

doi:10.1016/j.celrep.2019.07.063

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

Cell Rep. 2019 Aug 27;28(9):2317-2330.e8. doi: 10.1016/j.celrep.2019.07.063.

Authors

Nilanjana Chatterjee¹, Evangelos Pazarentzos², Manasi K Mayekar², Philippe Gui², David V Allegakoen², Gorjan Hrustanovic², Victor Olivas², Luping Lin², Erik Verschueren³, Jeffrey R Johnson³, Matan Hofree⁴, Jenny J Yan², Billy W Newton³, John V Dollen³, Charles H Earnshaw⁵, Jennifer Flanagan², Elton Chan², Saurabh Asthana⁶, Trey Ideker⁴, Wei Wu², Junji Suzuki⁷, Benjamin A Barad⁸, Yuriy Kirichok⁷, James S Fraser⁸, William A Weiss⁹, Nevan J Krogan³, Asmin Tulpule⁶, Amit J Sabnis⁶, Trever G Bivona¹⁰

Affiliations

¹ 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. Electronic address: [email protected].
² 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.
³ 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.
⁴ Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
⁶ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
⁷ Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁹ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ 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. Electronic address: [email protected].

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.

Keywords: NF-κB; NKAP; PDHK1; PTEN; cancer; metabolism; protein phosphatase; signaling; synthetic lethality.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Female
Glycolysis
HEK293 Cells
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
NF-kappa B / metabolism
Neoplasms / genetics
Neoplasms / metabolism*
Neoplasms / pathology
PTEN Phosphohydrolase / economics
PTEN Phosphohydrolase / genetics*
PTEN Phosphohydrolase / metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics*
Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism
Repressor Proteins / metabolism

Substances

NF-kappa B
NKAP protein, human
PDK1 protein, human
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Repressor Proteins
PTEN Phosphohydrolase

Abstract

Publication types

MeSH terms

Substances

Grants and funding