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 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.

ERRα Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1α-Elevated Melanomas

“…Given that suppression of ERRα does not significantly compromise the antioxidant systems, the compensatory glycolytic reprogramming associated with PGC1α depletion is likely to be prevented. Although PGC1α/ERRα complex in prostate cancers has been demonstrated to elicit a catabolic state that compromises metastatic spread (14), yet ERRα in melanoma cells seems to segregate these PGC1α functions with regard to metastatic regulation. Furthermore, while PGC1α triggers a metabolism-independent transcription profile that suppresses melanoma metastasis (5), our data indicates that ERRα-mediated control of genes promoting oxidative metabolism is not involved in this regulatory circuit; however, these ERRα regulated genes are required to support melanoma cell proliferation (Fig.…”

“…Further, the ERRα/PGC1α complex suppresses one-carbon metabolism in response to AMPK stimulation, thus rendering breast cancer cells more vulnerable to anti-folate drugs such as methotrexate (13). On the other hand, in prostate cancer, ERRα has been found to promote catabolic metabolism that subsequently suppresses the metastatic ability (14). In melanoma, it is however not clear to what extent ERRα functionally contribute to tumor growth.…”

Rethinking HSF1 in Stress, Development, and Organismal Health

“…FBXW7 has been suggested to stabilize nuclear-localized HSF1 for transcription in the absence of stress, thus promoting the metastatic potential of cancer cells [20]. On the contrary, PGC1α, which co-occupies with HSF1 at non HSR loci and represses HSF1 transcriptional activity, [17] decreases metastasis in prostate cancer [51]. It will therefore be of interest to determine how HSF1 is involved in the metabolic regulation of cancer by PGC1α, and together with other identified HSF1 regulators and interaction partners, to understand how HSF1 regulates the pro-growth program in development, metabolism and cancer.…”

El cáncer visto desde la mirilla metabólica

“…En nuestro caso, la bioinformática nos ha proporcionado una herramienta para realizar investigación de calidad en metabolismo del cáncer, a invertir mejor los recursos de que disponemos en candidatos sobre los que tenemos suficientes evidencias preliminares, y a reducir el bache que existe entre el descubrimiento fundamental y su traslación. Como ejemplo del potencial de esta aproximación experimental, uno de nuestros primeros trabajos parte de la bioinformática como método para la identificación de un regulador del metabolismo en cáncer de próstata (8). En este estudio nos preguntamos qué reguladores transcripcionales podrían contribuir a la reprogramación metabólica en esta enfermedad.…”