Format

Send to

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

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

Author information

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: nilanjana.chatterjee@ucsf.edu.
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: trever.bivona@ucsf.edu.

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

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center