The metabolic co-regulator PGC1α suppresses prostate cancer metastasis

Veronica Torrano; Lorea Valcarcel-Jimenez; Ana Rosa Cortazar; Xiaojing Liu; Jelena Urosevic; Mireia Castillo-Martin; Sonia Fernández-Ruiz; Giampaolo Morciano; Alfredo Caro-Maldonado; Marc Guiu; Patricia Zúñiga-García; Mariona Graupera; Anna Bellmunt; Pahini Pandya; Mar Lorente; Natalia Martín-Martín; James David Sutherland; Pilar Sanchez-Mosquera; Laura Bozal-Basterra; Amaia Zabala-Letona; Amaia Arruabarrena-Aristorena; Antonio Berenguer; Nieves Embade; Aitziber Ugalde-Olano; Isabel Lacasa-Viscasillas; Ana Loizaga-Iriarte; Miguel Unda-Urzaiz; Nikolaus Schultz; Ana Maria Aransay; Victoria Sanz-Moreno; Rosa Barrio; Guillermo Velasco; Paolo Pinton; Carlos Cordon-Cardo; Jason W. Locasale; Roger R. Gomis; Arkaitz Carracedo

doi:10.1038/ncb3357

The metabolic co-regulator PGC1α suppresses prostate cancer metastasis

Veronica Torrano, Lorea Valcarcel-Jimenez, Ana Rosa Cortazar, Xiaojing Liu, Jelena Urosevic, Mireia Castillo-Martin, Sonia Fernández-Ruiz, Giampaolo Morciano, Alfredo Caro-Maldonado, Marc Guiu, Patricia Zúñiga-García, Mariona Graupera, Anna Bellmunt, Pahini Pandya, Mar Lorente, Natalia Martín-Martín, James David Sutherland, Pilar Sanchez-Mosquera, Laura Bozal-Basterra, Amaia Zabala-LetonaAmaia Arruabarrena-Aristorena, Antonio Berenguer, Nieves Embade, Aitziber Ugalde-Olano, Isabel Lacasa-Viscasillas, Ana Loizaga-Iriarte, Miguel Unda-Urzaiz, Nikolaus Schultz, Ana Maria Aransay, Victoria Sanz-Moreno, Rosa Barrio, Guillermo Velasco, Paolo Pinton, Carlos Cordon-Cardo, Jason W. Locasale, Roger R. Gomis, Arkaitz Carracedo^*

^*Corresponding author for this work

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

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Abstract

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.

Original language	English
Pages (from-to)	645-656
Number of pages	12
Journal	Nature Cell Biology
Volume	18
Issue number	6
Early online date	23 May 2016
DOIs	https://doi.org/10.1038/ncb3357
Publication status	Published - 30 Jun 2016

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The metabolic co-regulator_TORRANO_Accepted13APril2016_GREEN AAMAccepted author manuscript, 4.2 MB

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884178/

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Torrano, V., Valcarcel-Jimenez, L., Cortazar, A. R., Liu, X., Urosevic, J., Castillo-Martin, M., Fernández-Ruiz, S., Morciano, G., Caro-Maldonado, A., Guiu, M., Zúñiga-García, P., Graupera, M., Bellmunt, A., Pandya, P., Lorente, M., Martín-Martín, N., David Sutherland, J., Sanchez-Mosquera, P., Bozal-Basterra, L., ... Carracedo, A. (2016). The metabolic co-regulator PGC1α suppresses prostate cancer metastasis. Nature Cell Biology, 18(6), 645-656. https://doi.org/10.1038/ncb3357

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title = "The metabolic co-regulator PGC1α suppresses prostate cancer metastasis",

abstract = "Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.",

author = "Veronica Torrano and Lorea Valcarcel-Jimenez and Cortazar, {Ana Rosa} and Xiaojing Liu and Jelena Urosevic and Mireia Castillo-Martin and Sonia Fern{\'a}ndez-Ruiz and Giampaolo Morciano and Alfredo Caro-Maldonado and Marc Guiu and Patricia Z{\'u}{\~n}iga-Garc{\'i}a and Mariona Graupera and Anna Bellmunt and Pahini Pandya and Mar Lorente and Natalia Mart{\'i}n-Mart{\'i}n and {David Sutherland}, James and Pilar Sanchez-Mosquera and Laura Bozal-Basterra and Amaia Zabala-Letona and Amaia Arruabarrena-Aristorena and Antonio Berenguer and Nieves Embade and Aitziber Ugalde-Olano and Isabel Lacasa-Viscasillas and Ana Loizaga-Iriarte and Miguel Unda-Urzaiz and Nikolaus Schultz and Aransay, {Ana Maria} and Victoria Sanz-Moreno and Rosa Barrio and Guillermo Velasco and Paolo Pinton and Carlos Cordon-Cardo and Locasale, {Jason W.} and Gomis, {Roger R.} and Arkaitz Carracedo",

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Torrano, V, Valcarcel-Jimenez, L, Cortazar, AR, Liu, X, Urosevic, J, Castillo-Martin, M, Fernández-Ruiz, S, Morciano, G, Caro-Maldonado, A, Guiu, M, Zúñiga-García, P, Graupera, M, Bellmunt, A, Pandya, P, Lorente, M, Martín-Martín, N, David Sutherland, J, Sanchez-Mosquera, P, Bozal-Basterra, L, Zabala-Letona, A, Arruabarrena-Aristorena, A, Berenguer, A, Embade, N, Ugalde-Olano, A, Lacasa-Viscasillas, I, Loizaga-Iriarte, A, Unda-Urzaiz, M, Schultz, N, Aransay, AM, Sanz-Moreno, V, Barrio, R, Velasco, G, Pinton, P, Cordon-Cardo, C, Locasale, JW, Gomis, RR & Carracedo, A 2016, 'The metabolic co-regulator PGC1α suppresses prostate cancer metastasis', Nature Cell Biology, vol. 18, no. 6, pp. 645-656. https://doi.org/10.1038/ncb3357

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T1 - The metabolic co-regulator PGC1α suppresses prostate cancer metastasis

AU - Torrano, Veronica

AU - Valcarcel-Jimenez, Lorea

AU - Cortazar, Ana Rosa

AU - Liu, Xiaojing

AU - Urosevic, Jelena

AU - Castillo-Martin, Mireia

AU - Fernández-Ruiz, Sonia

AU - Morciano, Giampaolo

AU - Caro-Maldonado, Alfredo

AU - Guiu, Marc

AU - Zúñiga-García, Patricia

AU - Graupera, Mariona

AU - Bellmunt, Anna

AU - Pandya, Pahini

AU - Lorente, Mar

AU - Martín-Martín, Natalia

AU - David Sutherland, James

AU - Sanchez-Mosquera, Pilar

AU - Bozal-Basterra, Laura

AU - Zabala-Letona, Amaia

AU - Arruabarrena-Aristorena, Amaia

AU - Berenguer, Antonio

AU - Embade, Nieves

AU - Ugalde-Olano, Aitziber

AU - Lacasa-Viscasillas, Isabel

AU - Loizaga-Iriarte, Ana

AU - Unda-Urzaiz, Miguel

AU - Schultz, Nikolaus

AU - Aransay, Ana Maria

AU - Sanz-Moreno, Victoria

AU - Barrio, Rosa

AU - Velasco, Guillermo

AU - Pinton, Paolo

AU - Cordon-Cardo, Carlos

AU - Locasale, Jason W.

AU - Gomis, Roger R.

AU - Carracedo, Arkaitz

PY - 2016/6/30

Y1 - 2016/6/30

N2 - Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.

AB - Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.

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U2 - 10.1038/ncb3357

DO - 10.1038/ncb3357

M3 - Article

AN - SCOPUS:84969816000

SN - 1465-7392

VL - 18

SP - 645

EP - 656

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 6

ER -

The metabolic co-regulator PGC1α suppresses prostate cancer metastasis

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