GSE75193
A metabolic co-regulator bioinformatics screen reveals that PGC1a suppresses prostate cancer metastasis
The current view of cellular transformation and cancer progression supports the notion that cancer cells must reprogram their metabolism in order to survive and progress in different microenvironments. 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 PGC1a suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1a is consistently  down-regulated in multiple prostate cancer patient datasets and its alteration is associated with reduced disease-free survival and metastasis. Genetically engineered mouse model studies revealed that compound prostate epithelium-specific deletion of Pgc1a and Pten promotes prostate cancer progression and metastasis, whereas, conversely, PGC1a expression in cell lines inhibits the pre-existing metastatic capacity. Through the application of integrative metabolomics and transcriptomics we demonstrate that PGC1a expression in prostate cancer is sufficient to elicit a global metabolic rewiring that opposes cell growth, consisting of sustained oxidative metabolism at the expense of anabolism. This metabolic program is regulated downstream the Oestrogen-related receptor alpha (ERRa), and PGC1a mutants lacking ERRa activation capacity lack metabolic rewiring capacity and metastasissuppressive function. Importantly, an ERRa signature in prostate cancer recapitulates the prognostic features of PGC1A. Our findings uncover an unprecedented causal contribution of PGC1a to the metabolic switch in prostate cancer and to the suppression of metastatic dissemination. Overall design: Total RNA was isolated from prostate cancer cell line PC3 expressing or not PGC1a (for induction, cells were treated with doxycycline for 2 passages)