Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

N. Chatterjee, E. Pazarentzos, G. Hrustanovic, L. Lin, E. Verschueren, J.R. Johnson, M. Hofree, J.J. Yan, V. Olivas, B.W. Newton, J.V. Dollen, C.H. Earnshaw, J. Flanagan, E. Chan, S. Asthana, T. Ideker, W. Wu, M.K. Mayekar, J. Suzuki, B. BaradY. Kirichok, J. Fraser, W.A. Weiss, N.J. Krogan, A. Tulpule, A.J. Sabnis, T.G. Bivona

Research output: Working paper/preprintPreprint

Abstract

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. The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Original languageEnglish
DOIs
StatePublished - 2018

Publication series

NamebioRxiv
PublisherbioRxiv
ISSN (Print)2692-8205

Bibliographical note

Export Date: 27 November 2022

Correspondence Address: Bivona, T.G.; Department of Medicine, United States; email: trever.bivona@ucsf.edu

Keywords

  • cancer
  • metabolism
  • NFκB
  • NKAP
  • PDHK1
  • protein phosphatase
  • PTEN
  • signaling
  • synthetic lethality
  • Cancer Biology

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