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 PGC1α suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is down-regulated in prostate cancer and associated to 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.
Highlights
We focused on transcriptional co-regulators of metabolism[17] that i) were consistently altered in several publicly available prostate cancer (PCa) datasets[18,19,20,21,22,23,24], and ii) were associated with reduced time to recurrence and disease aggressiveness
The analysis revealed 10 co-regulators in the set of study with significant differential expression in PCa compared to non-neoplastic prostate tissue (Fig. 1a, Supplementary Fig. 1A)
In this study we provide a comprehensive analysis of master transcriptional co-regulators of metabolism in PCa
Summary
A bioinformatics screen identifies PGC1A as metabolic co-regulator associated to prostate cancer progression. The analysis revealed 10 co-regulators in the set of study with significant differential expression in PCa compared to non-neoplastic prostate tissue (Fig. 1a, Supplementary Fig. 1A) We extended this observation to four additional datasets[18,21,23,24] in which there was available data for non-tumoural and PCa tissues. Through the analysis of publicly available datasets[22], we could demonstrate that the transcript levels of PGC1A in metastatic cell lines are comparable to those observed in human metastatic PCa specimens and vastly reduced compared to PGC1α-positive melanoma cells (Fig. 3a, Supplementary Fig. 3B). Our data provides a molecular mechanism by which ERRα activation downstream PGC1α promotes a metabolic rewiring that suppresses PCa proliferation and metastasis
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