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

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2019 Aug 29

PMID 31461649

Citations 7

Authors

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

Soon will be listed here.

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.

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