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Nature Research, Nature Cell Biology, 6(18), p. 645-656, 2016

DOI: 10.1038/ncb3357

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The metabolic co-regulator PGC1α suppresses prostate cancer metastasis

Journal article published in 2016 by Veronica Torrano, Lorea Valcarcel Jimenez ORCID, Ana Rosa Cortazar, Xiaojing Liu, Jelena Urosevic, Mireia Castillo Martin, Sonia Fernández Ruiz, Giampaolo Morciano, Alfredo Caro Maldonado, Marc Guiu, Patricia Zúñiga García ORCID, Mariona Graupera, James David Sutherland, Anna Bellmunt, Pahini Pandya and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.