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.
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Torrano
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Lorea
authors.initials: L
authors.lastname: Valcarcel-Jimenez
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Ana Rosa
authors.initials: AR
authors.lastname: Cortazar
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Catalonia, Spain.
authors.forename: Jelena
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authors.lastname: Urosevic
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Pathology, Fundação Champalimaud, Lisboa, Portugal.
authors.forename: Mireia
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authors.lastname: Castillo-Martin
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Ruiz
authors.affiliation: Dept. of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Morciano
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Caro-Maldonado
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Catalonia, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Guiu
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Patricia
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authors.lastname: Zúñiga-García
authors.affiliation: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l'Hospitalet 199-203, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Catalonia, Spain.
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authors.lastname: Bellmunt
authors.affiliation: 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.
authors.forename: Pahini
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authors.lastname: Pandya
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and Instituto de Investigaciones Sanitarias San Carlos (IdISSC) 28040 Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Lorente
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Martín-Martín
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: James David
authors.initials: JD
authors.lastname: Sutherland
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sanchez-Mosquera
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Bozal-Basterra
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Zabala-Letona
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Arruabarrena-Aristorena
authors.affiliation: Biostatistics / Bioinformatics Unit, - IRB Barcelona, Parc Científic de Barcelona, 08028 Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Berenguer
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Embade
authors.affiliation: Department of Pathology, Basurto University Hospital, 48013 Bilbao, Spain.
authors.forename: Aitziber
authors.initials: A
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authors.affiliation: Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lacasa-Viscasillas
authors.affiliation: Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Loizaga-Iriarte
authors.affiliation: Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Unda-Urzaiz
authors.affiliation: Computational Biology, Memorial Sloan-Kettering Cancer Center, NY, 10065, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: 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.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sanz-Moreno
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Barrio
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and Instituto de Investigaciones Sanitarias San Carlos (IdISSC) 28040 Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Velasco
authors.affiliation: Dept. of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Italy.
authors.forename: Paolo
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authors.lastname: Pinton
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Catalonia, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Gomis
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 801 bld., 48160 Derio, Bizkaia, Spain.|Ikerbasque, Basque foundation for science, 48011 Bilbao, Spain.|Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), P. O. Box 644, E-48080 Bilbao, Spain.
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011960:Receptors, Estrogen / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D006360:Heat-Shock Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C486497:PPARGC1A protein, human; C485290:Ppargc1a protein, mouse