학술논문
The metabolic co-regulator PGC1α suppresses prostate cancer metastasis
Document Type
Report
Author
Torrano, Veronica; Valcarcel-Jimenez, Lorea; Cortazar, Ana Rosa; Liu, Xiaojing; Urosevic, Jelena; Castillo-Martin, Mireia; Fernandez-Ruiz, Sonia; Morciano, Giampaolo; Caro-Maldonado, Alfredo; Guiu, Marc; Zuniga-Garcia, Patricia; Graupera, Mariona; Bellmunt, Anna; Pandya, Pahini; Lorente, Mar; Martin-Martin, Natalia; Sutherland, James David; Sanchez-Mosquera, Pilar; Bozal-Basterra, Laura; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Berenguer, Antonio; Embade, Nieves; Ugalde-Olano, Aitziber; Lacasa-Viscasillas, Isabel; Loizaga-Iriarte, Ana; Unda-Urzaiz, Miguel; Schultz, Nikolaus; Aransay, Ana Maria; Sanz-Moreno, Victoria; Barrio, Rosa; Velasco, Guillermo; Pinton, Paolo; Cordon-Cardo, Carlos; Locasale, Jason W.; Gomis, Roger R.; Carracedo, Arkaitz
Source
Nature Cell Biology. June 1, 2016, p645, 23 p.
Subject
Language
English
ISSN
1465-7392
Abstract
The metabolic switch in cancer encompasses a plethora of discrete enzymatic activities that must be coordinately altered to ensure the generation of biomass, reductive power and the remodelling of the [...]
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.
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.