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; M. Hofree; Jenny J. Yan; Billy W. Newton; John V. Dollen; Charles H. Earnshaw; Jennifer Flanagan; E. Chan; Saurabh Asthana; Trey Ideker; Wei Wu; J. Suzuki; Benjamin A. Barad; Y. Kirichok; James S. Fraser; William A. Weiss; Nevan J. Krogan; A. 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

Nilanjana Chatterjee^*, Evangelos Pazarentzos, Manasi K. Mayekar, Philippe Gui, David V. Allegakoen, Gorjan Hrustanovic, Victor Olivas, Luping Lin, Erik Verschueren, Jeffrey R. Johnson, M. Hofree, Jenny J. Yan, Billy W. Newton, John V. Dollen, Charles H. Earnshaw, Jennifer Flanagan, E. Chan, Saurabh Asthana, Trey Ideker, Wei WuJ. Suzuki, Benjamin A. Barad, Y. Kirichok, James S. Fraser, William A. Weiss, Nevan J. Krogan, A. Tulpule, Amit J. Sabnis, Trever G. Bivona

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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. The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers.

Original language	American English
Pages (from-to)	2317-2330.e8
Journal	Cell Reports
Volume	28
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2019.07.063
State	Published - 27 Aug 2019
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank all members of the Bivona laboratory for critical review of the manuscript and acknowledge funding support from NIH/NCI grants U54CA224081, R01CA204302, R01CA211052, and R01CA169338 and the Pew Foundation and Stewart Foundation (to T.G.B.); U54 CA209891 (to N.J.K.); R01GM123159 (to J.S.F.); R01GM118939 (to Y.K.); and NIH/NCI T32CA108462-14 (to N.C.). We thank Timothy Fouts and Jeffrey Meshulam at Profectus Biosciences, Inc. for generously providing PBS-1086. We thank Bhagyashri Burgute and Angelika Noegel at the University of Cologne, Germany, for kindly providing the NKAP mouse mAb (K85-80-5). We thank Albertas Navickas and Hani Goodarzi at UCSF for the hypoxia chamber. N.C. E.P. and T.G.B. conceived and designed the experiments and analyzed the data. N.C. E.P. M.K.M. P.G. D.V.A. G.H. V.O. J.J.Y. L.L. C.H.E. J.F. and E.C. performed the experiments. S.A. and W.W. analyzed microarray data. T.I. M.H. and W.A.W. analyzed TCGA tumor data. J.S. performed time-lapse microscopy and analyzed the data. B.A.B. helped N.C. with PTEN purification. E.V. J.R.J. B.W.N. J.V.D. and N.J.K. performed phospho-proteomics screen and analyzed the data. N.C. E.P. A.J.S. and T.G.B. wrote the manuscript with input from all authors. T.G.B. is an advisor to Array Biopharma, Revolution Medicines, Novartis, AstraZeneca, Takeda, Springworks, and Jazz Pharmaceuticals and receives research funding from Novartis and Revolution Medicines.

Funding Information:
We would like to thank all members of the Bivona laboratory for critical review of the manuscript and acknowledge funding support from NIH/NCI grants U54CA224081 , R01CA204302 , R01CA211052 , and R01CA169338 and the Pew Foundation and Stewart Foundation (to T.G.B.); U54 CA209891 (to N.J.K.); R01GM123159 (to J.S.F.); R01GM118939 (to Y.K.); and NIH / NCI T32CA108462-14 (to N.C.). We thank Timothy Fouts and Jeffrey Meshulam at Profectus Biosciences, Inc., for generously providing PBS-1086. We thank Bhagyashri Burgute and Angelika Noegel at the University of Cologne, Germany, for kindly providing the NKAP mouse mAb (K85-80-5). We thank Albertas Navickas and Hani Goodarzi at UCSF for the hypoxia chamber.

Publisher Copyright:
© 2019 The Author(s)

Keywords

NF-κB
NKAP
PDHK1
PTEN
cancer
metabolism
protein phosphatase
signaling
synthetic lethality

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2019.07.063

Cite this

Chatterjee, N., Pazarentzos, E., Mayekar, M. K., Gui, P., Allegakoen, D. V., Hrustanovic, G., Olivas, V., Lin, L., Verschueren, E., Johnson, J. R., Hofree, M., Yan, J. J., Newton, B. W., Dollen, J. V., Earnshaw, C. H., Flanagan, J., Chan, E., Asthana, S., Ideker, T., ... Bivona, T. G. (2019). Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers. Cell Reports, 28(9), 2317-2330.e8. https://doi.org/10.1016/j.celrep.2019.07.063

@article{16ec018da804453e8a3c4e30826cbeb5,

title = "Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers",

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. The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers.",

keywords = "NF-κB, NKAP, PDHK1, PTEN, cancer, metabolism, protein phosphatase, signaling, synthetic lethality",

author = "Nilanjana Chatterjee and Evangelos Pazarentzos and Mayekar, {Manasi K.} and Philippe Gui and Allegakoen, {David V.} and Gorjan Hrustanovic and Victor Olivas and Luping Lin and Erik Verschueren and Johnson, {Jeffrey R.} and M. Hofree and Yan, {Jenny J.} and Newton, {Billy W.} and Dollen, {John V.} and Earnshaw, {Charles H.} and Jennifer Flanagan and E. Chan and Saurabh Asthana and Trey Ideker and Wei Wu and J. Suzuki and Barad, {Benjamin A.} and Y. Kirichok and Fraser, {James S.} and Weiss, {William A.} and Krogan, {Nevan J.} and A. Tulpule and Sabnis, {Amit J.} and Bivona, {Trever G.}",

note = "Funding Information: We would like to thank all members of the Bivona laboratory for critical review of the manuscript and acknowledge funding support from NIH/NCI grants U54CA224081, R01CA204302, R01CA211052, and R01CA169338 and the Pew Foundation and Stewart Foundation (to T.G.B.); U54 CA209891 (to N.J.K.); R01GM123159 (to J.S.F.); R01GM118939 (to Y.K.); and NIH/NCI T32CA108462-14 (to N.C.). We thank Timothy Fouts and Jeffrey Meshulam at Profectus Biosciences, Inc. for generously providing PBS-1086. We thank Bhagyashri Burgute and Angelika Noegel at the University of Cologne, Germany, for kindly providing the NKAP mouse mAb (K85-80-5). We thank Albertas Navickas and Hani Goodarzi at UCSF for the hypoxia chamber. N.C. E.P. and T.G.B. conceived and designed the experiments and analyzed the data. N.C. E.P. M.K.M. P.G. D.V.A. G.H. V.O. J.J.Y. L.L. C.H.E. J.F. and E.C. performed the experiments. S.A. and W.W. analyzed microarray data. T.I. M.H. and W.A.W. analyzed TCGA tumor data. J.S. performed time-lapse microscopy and analyzed the data. B.A.B. helped N.C. with PTEN purification. E.V. J.R.J. B.W.N. J.V.D. and N.J.K. performed phospho-proteomics screen and analyzed the data. N.C. E.P. A.J.S. and T.G.B. wrote the manuscript with input from all authors. T.G.B. is an advisor to Array Biopharma, Revolution Medicines, Novartis, AstraZeneca, Takeda, Springworks, and Jazz Pharmaceuticals and receives research funding from Novartis and Revolution Medicines. Funding Information: We would like to thank all members of the Bivona laboratory for critical review of the manuscript and acknowledge funding support from NIH/NCI grants U54CA224081 , R01CA204302 , R01CA211052 , and R01CA169338 and the Pew Foundation and Stewart Foundation (to T.G.B.); U54 CA209891 (to N.J.K.); R01GM123159 (to J.S.F.); R01GM118939 (to Y.K.); and NIH / NCI T32CA108462-14 (to N.C.). We thank Timothy Fouts and Jeffrey Meshulam at Profectus Biosciences, Inc., for generously providing PBS-1086. We thank Bhagyashri Burgute and Angelika Noegel at the University of Cologne, Germany, for kindly providing the NKAP mouse mAb (K85-80-5). We thank Albertas Navickas and Hani Goodarzi at UCSF for the hypoxia chamber. Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = aug,

day = "27",

doi = "10.1016/j.celrep.2019.07.063",

language = "American English",

volume = "28",

pages = "2317--2330.e8",

journal = "Cell Reports",

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Chatterjee, N, Pazarentzos, E, Mayekar, MK, Gui, P, Allegakoen, DV, Hrustanovic, G, Olivas, V, Lin, L, Verschueren, E, Johnson, JR, Hofree, M, Yan, JJ, Newton, BW, Dollen, JV, Earnshaw, CH, Flanagan, J, Chan, E, Asthana, S, Ideker, T, Wu, W, Suzuki, J, Barad, BA, Kirichok, Y, Fraser, JS, Weiss, WA, Krogan, NJ, Tulpule, A, Sabnis, AJ & Bivona, TG 2019, 'Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers', Cell Reports, vol. 28, no. 9, pp. 2317-2330.e8. https://doi.org/10.1016/j.celrep.2019.07.063

TY - JOUR

T1 - Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers

AU - Chatterjee, Nilanjana

AU - Pazarentzos, Evangelos

AU - Mayekar, Manasi K.

AU - Gui, Philippe

AU - Allegakoen, David V.

AU - Hrustanovic, Gorjan

AU - Olivas, Victor

AU - Lin, Luping

AU - Verschueren, Erik

AU - Johnson, Jeffrey R.

AU - Hofree, M.

AU - Yan, Jenny J.

AU - Newton, Billy W.

AU - Dollen, John V.

AU - Earnshaw, Charles H.

AU - Flanagan, Jennifer

AU - Chan, E.

AU - Asthana, Saurabh

AU - Ideker, Trey

AU - Wu, Wei

AU - Suzuki, J.

AU - Barad, Benjamin A.

AU - Kirichok, Y.

AU - Fraser, James S.

AU - Weiss, William A.

AU - Krogan, Nevan J.

AU - Tulpule, A.

AU - Sabnis, Amit J.

AU - Bivona, Trever G.

N1 - Funding Information: We would like to thank all members of the Bivona laboratory for critical review of the manuscript and acknowledge funding support from NIH/NCI grants U54CA224081, R01CA204302, R01CA211052, and R01CA169338 and the Pew Foundation and Stewart Foundation (to T.G.B.); U54 CA209891 (to N.J.K.); R01GM123159 (to J.S.F.); R01GM118939 (to Y.K.); and NIH/NCI T32CA108462-14 (to N.C.). We thank Timothy Fouts and Jeffrey Meshulam at Profectus Biosciences, Inc. for generously providing PBS-1086. We thank Bhagyashri Burgute and Angelika Noegel at the University of Cologne, Germany, for kindly providing the NKAP mouse mAb (K85-80-5). We thank Albertas Navickas and Hani Goodarzi at UCSF for the hypoxia chamber. N.C. E.P. and T.G.B. conceived and designed the experiments and analyzed the data. N.C. E.P. M.K.M. P.G. D.V.A. G.H. V.O. J.J.Y. L.L. C.H.E. J.F. and E.C. performed the experiments. S.A. and W.W. analyzed microarray data. T.I. M.H. and W.A.W. analyzed TCGA tumor data. J.S. performed time-lapse microscopy and analyzed the data. B.A.B. helped N.C. with PTEN purification. E.V. J.R.J. B.W.N. J.V.D. and N.J.K. performed phospho-proteomics screen and analyzed the data. N.C. E.P. A.J.S. and T.G.B. wrote the manuscript with input from all authors. T.G.B. is an advisor to Array Biopharma, Revolution Medicines, Novartis, AstraZeneca, Takeda, Springworks, and Jazz Pharmaceuticals and receives research funding from Novartis and Revolution Medicines. Funding Information: We would like to thank all members of the Bivona laboratory for critical review of the manuscript and acknowledge funding support from NIH/NCI grants U54CA224081 , R01CA204302 , R01CA211052 , and R01CA169338 and the Pew Foundation and Stewart Foundation (to T.G.B.); U54 CA209891 (to N.J.K.); R01GM123159 (to J.S.F.); R01GM118939 (to Y.K.); and NIH / NCI T32CA108462-14 (to N.C.). We thank Timothy Fouts and Jeffrey Meshulam at Profectus Biosciences, Inc., for generously providing PBS-1086. We thank Bhagyashri Burgute and Angelika Noegel at the University of Cologne, Germany, for kindly providing the NKAP mouse mAb (K85-80-5). We thank Albertas Navickas and Hani Goodarzi at UCSF for the hypoxia chamber. Publisher Copyright: © 2019 The Author(s)

PY - 2019/8/27

Y1 - 2019/8/27

N2 - 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. The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers.

AB - 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. The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers.

KW - NF-κB

KW - NKAP

KW - PDHK1

KW - PTEN

KW - cancer

KW - metabolism

KW - protein phosphatase

KW - signaling

KW - synthetic lethality

UR - http://www.scopus.com/inward/record.url?scp=85070920745&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.07.063

DO - 10.1016/j.celrep.2019.07.063

M3 - Article

C2 - 31461649

AN - SCOPUS:85070920745

SN - 2211-1247

VL - 28

SP - 2317-2330.e8

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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