Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer
- Étienne Audet-Walsh1,
- Catherine R. Dufour1,
- Tracey Yee1,
- Fatima Z. Zouanat2,
- Ming Yan1,
- Georges Kalloghlian2,
- Mathieu Vernier1,
- Maxime Caron3,
- Guillaume Bourque3,4,
- Eleonora Scarlata2,
- Lucie Hamel2,
- Fadi Brimo4,
- Armen G. Aprikian2,5,
- Jacques Lapointe6,7,
- Simone Chevalier2,5,8,9 and
- Vincent Giguère1,8,9,10
- 1Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada;
- 2Urologic Oncology Research Group, Cancer Research Program, Research Institute of the McGill University Health Centre (MUHC), Montréal, Québec H4A 3J1, Canada;
- 3Génome Québec Innovation Centre, McGill University, Montréal, Québec H3A 0G1, Canada;
- 4Department of Human Genetics, McGill University, Montréal, Québec H3A 1A3, Canada;
- 5Department of Pathology, McGill University and MUHC, Montréal, Québec H4A 3J1, Canada;
- 6Department of Surgery (Urology), McGill University and MUHC, Montréal, Québec H4A 3J1, Canada;
- 7Department of Oncology, McGill University and MUHC, Montréal, Québec H4A 3J1, Canada;
- 8Department of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada;
- 9Department of Oncology, McGill University, Montréal, Québec H3G 1Y6, Canada;
- 10Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada
- Corresponding author: vincent.giguere{at}mcgill.ca
Abstract
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.299958.117.
- Received April 3, 2017.
- Accepted June 19, 2017.
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