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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Gene Expression Omnibus
Gene Expression Omnibus
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.
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Journal of Cellular Physiology (2019)