Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer
| Autor: | Armen Aprikian, Simone Chevalier, Fatima Z. Zouanat, Jacques Lapointe, Ming Yan, Vincent Giguère, Fadi Brimo, Tracey Yee, Maxime Caron, Guillaume Bourque, Catherine R. Dufour, Mathieu Vernier, Georges Kalloghlian, Lucie Hamel, Eleonora Scarlata, Étienne Audet-Walsh |
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| Přispěvatelé: | McGill University = Université McGill [Montréal, Canada] |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Transcription Genetic [SDV]Life Sciences [q-bio] Regulator Biology 03 medical and health sciences Prostate cancer Genetics medicine Transcriptional regulation Humans PI3K/AKT/mTOR pathway ComputingMilieux_MISCELLANEOUS Cell Nucleus TOR Serine-Threonine Kinases RPTOR Prostatic Neoplasms DNA medicine.disease Research Papers Androgen receptor Gene Expression Regulation Neoplastic 030104 developmental biology Nuclear receptor Receptors Androgen Cancer research Androgens Disease Progression Signal transduction Developmental Biology Protein Binding Signal Transduction |
| Zdroj: | Genes and Development Genes and Development, Cold Spring Harbor Laboratory Press, 2017, 31 (12), pp.1228-1242. ⟨10.1101/gad.299958.117⟩ |
| ISSN: | 0890-9369 |
| DOI: | 10.1101/gad.299958.117⟩ |
| Popis: | Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgen-induced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa. |
| Databáze: | OpenAIRE |
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