RT Journal Article
SR Electronic
T1 Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 441295
DO 10.1101/441295
A1 Nilanjana Chatterjee
A1 Evangelos Pazarentzos
A1 Gorjan Hrustanovic
A1 Luping Lin
A1 Erik Verschueren
A1 Jeffrey R. Johnson
A1 Matan Hofree
A1 Jenny J. Yan
A1 Victor Olivas
A1 Billy W. Newton
A1 John V. Dollen
A1 Charles H. Earnshaw
A1 Jennifer Flanagan
A1 Elton Chan
A1 Saurabh Asthana
A1 Trey Ideker
A1 Wei Wu
A1 Manasi K. Mayekar
A1 Junji Suzuki
A1 Ben Barad
A1 Yuriy Kirichok
A1 James Fraser
A1 William A. Weiss
A1 Nevan J. Krogan
A1 Asmin Tulpule
A1 Amit J. Sabnis
A1 Trever G. Bivona
YR 2018
UL http://biorxiv.org/content/early/2018/10/11/441295.abstract
AB PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NFκ;B activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NFκB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.SIGNIFICANCE The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell death in vitro and tumor regression in vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers.