• An Erratum to this article was published on 29 June 2017

This article has been updated


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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  • 22 May 2017

    In the original version of this Article, the name of author James David Sutherland was coded wrongly, resulting in it being incorrect when exported to citation databases. This has now been corrected, though no visible changes will be apparent.


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Apologies to those whose related publications were not cited owing to space limitations. We would like to thank the following researchers: B. Spiegelman (Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA) for providing the Pgc1aLoxP mice; D. Santamaría and M. Barbacid (Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain) for technical help and advice with doxycycline-enriched diets in xenograft experiments; P. Puigserver (Department of Cell Biology, Harvard Medical School, and in the Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA) for providing Pgc1α-expressing constructs; B. Carver (Department of Surgery, Division of Urology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA) for help and advice with data set analysis, D. McDonnell (Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA) for providing mutant Pgc1αL2L3M-expressing constructs and M. D. Boyano (Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain) and A. Buqué (Medical Oncology Research Laboratory, Cruces Universtity Hospital, Bizkaia, Spain) for providing melanoma cell lines. The work of A.C. is supported by the Ramón y Cajal award, the Basque Department of Industry, Tourism and Trade (Etortek), health (2012111086) and education (PI2012-03), Marie Curie (277043), Movember, ISCIII (PI10/01484, PI13/00031), FERO VIII Fellowship and the European Research Council Starting Grant (336343). N.M.-M. is supported by the Spanish Association Against Cancer (AECC). A.C.-M. is supported by the MINECO postdoctoral program and the CIG program from the European commission (660191). A.A.-A. and L.V.-J. are supported by the Basque Government of Education. P.Pinton is grateful to C. degli Scrovegni for continuous support and the work in his laboratory was supported by the Italian Association for Cancer Research (AIRC: IG-14442), the Italian Ministry of Education, University and Research (COFIN no. 20129JLHSY_002, FIRB no. RBAP11FXBC_002, and Futuro in Ricerca no. RBFR10EGVP_001) and the Italian Ministry of Health. R.B. is supported by MINECO (BFU2014-52282-P, BFU2011-25986) and the Basque Government (PI2012/42). The work of V.S.-M. was supported by Cancer Research UK C33043/A12065; Royal Society RG110591. P.Pandya was supported by King’s Overseas Scholarship. Work by the group of G.V. was supported by grants from the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III (MINECO/ISCIII) together with the European Regional Development Fund (ERDF/FEDER): PS09/01401; PI12/02248 and PI15/00339, Fundación Mutua Madrileña and Fundació la Marató de TV3. C.C.-C. and M.C.-M. were financially supported by NIH P01CA087497. J.W.L. is supported by R00CA168997, R01CA193256 and R21CA201963 from the National Institutes of Health. Work in the M.Graupera laboratory was supported by SAF2014-59950-P from MINECO (Spain), 2014-SGR-725 from the Catalan Government, from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013/ (REA grant agreement 317250), and the Institute of Health Carlos III (ISC III) and the European Regional Development Fund (ERDF) under the integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE). J.U. is a Juan de la Cierva Researcher (MINECO). A.Bellmunt is a FPI-Severo Ochoa fellowship grantee (MINECO). R.R.G. research support was provided by the Spanish Government (MINECO) and FEDER grant SAF2013-46196, as well as the Generalitat de Catalunya AGAUR 2014-SGR grant 535.

Author information

Author notes

    • Veronica Torrano
    •  & Lorea Valcarcel-Jimenez

    These authors contributed equally to this work.

    • Jason W. Locasale
    •  & Roger R. Gomis

    These authors jointly supervised this work.


  1. CIC bioGUNE, Bizkaia Technology Park, Building 801A, 48160 Derio, Bizkaia, Spain

    • Veronica Torrano
    • , Lorea Valcarcel-Jimenez
    • , Ana Rosa Cortazar
    • , Sonia Fernández-Ruiz
    • , Alfredo Caro-Maldonado
    • , Patricia Zúñiga-García
    • , Natalia Martín-Martín
    • , James David Sutherland
    • , Pilar Sanchez-Mosquera
    • , Laura Bozal-Basterra
    • , Amaia Zabala-Letona
    • , Amaia Arruabarrena-Aristorena
    • , Nieves Embade
    • , Ana Maria Aransay
    • , Rosa Barrio
    •  & Arkaitz Carracedo
  2. Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA

    • Xiaojing Liu
    •  & Jason W. Locasale
  3. Oncology Programme, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Catalonia, Spain

    • Jelena Urosevic
    • , Marc Guiu
    • , Anna Bellmunt
    •  & Roger R. Gomis
  4. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Mireia Castillo-Martin
    •  & Carlos Cordon-Cardo
  5. Department of Pathology, Fundação Champalimaud, 1400-038 Lisboa, Portugal

    • Mireia Castillo-Martin
  6. Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, 44100, Italy

    • Giampaolo Morciano
    •  & Paolo Pinton
  7. Vascular Signalling Laboratory, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l’Hospitalet 199-203, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

    • Mariona Graupera
  8. Tumour Plasticity Team, Randall Division of Cell and Molecular Biophysics, King’s College London, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK

    • Pahini Pandya
    •  & Victoria Sanz-Moreno
  9. Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain

    • Mar Lorente
    •  & Guillermo Velasco
  10. Biostatistics/Bioinformatics Uni, IRB Barcelona, Parc Científic de Barcelona, 08028 Barcelona, Spain

    • Antonio Berenguer
  11. Department of Pathology, Basurto University Hospital, 48013 Bilbao, Spain

    • Aitziber Ugalde-Olano
  12. Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain

    • Isabel Lacasa-Viscasillas
    • , Ana Loizaga-Iriarte
    •  & Miguel Unda-Urzaiz
  13. Computational Biology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA

    • Nikolaus Schultz
  14. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)

    • Ana Maria Aransay
  15. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

    • Roger R. Gomis
  16. Ikerbasque, Basque Foundation for Science, 48011 Bilbao, Spain

    • Arkaitz Carracedo
  17. Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), PO Box 644, E-48080 Bilbao, Spain

    • Arkaitz Carracedo


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V.T. and L.V.-J. performed all in vitro and in vivo experiments, unless specified otherwise. A.R.C. carried out the bioinformatic and biostatistical analysis. A.Berenguer and N.S. provided support and advice in data set retrieval and normalization. S.F.-R. performed the histochemical stainings. P.S.-M. and S.F.-R. performed genotyping analyses. X.L. and J.W.L. contributed to the experimental design and executed the metabolomic analyses. G.M. and P.Pinton performed the biochemical ATP measurement in vitro and mitochondria analysis. G.V., P.Z.-G. and M.L. performed or coordinated (G.V.) subcutaneous xenograft experiments. J.U., A.Bellmunt, M.Guiu and R.R.G. performed or coordinated (R.R.G.) the intra-cardiac and intra-tibial metastasis assays. R.R.G. contributed to the design of the patient gene signature analysis. M.Graupera carried out microvessel staining and quantifications. P.Pandya and V.S.-M. provided technical advice and contributed to in vitro analysis. N.M.-M., A.A.-A. and A.Z.-L. contributed to the experimental design and discussion. A.C.-M. and N.E. performed Seahorse assays. J.D.S. and R.B. performed or coordinated (R.B.) the cloning of Pgc1a in lentiviral vectors. C.C.-C. and M.C.-M. carried out the pathological analysis and scoring of the xenografts and GEMMs. A.U.-O., I.L.-V., A.L.-I. and M.U.-U. provided BPH and PCa samples for gene expression analysis from Basurto University Hospital. A.M.A. contributed to the discussion of the results. A.C. directed the project, contributed to data analysis and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Arkaitz Carracedo.

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