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2017
Audet-Walsh, Étienne; Dufour, Catherine R; Yee, Tracey; Zouanat, Fatima Z; Yan, Ming; Kalloghlian, Georges; Vernier, Mathieu; Caron, Maxime; Bourque, Guillaume; Scarlata, Eleonora; Hamel, Lucie; Brimo, Fadi; Aprikian, Armen G; Lapointe, Jacques; Chevalier, Simone; Giguère, Vincent
Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer Journal Article
In: Genes & Development, vol. 31, no. 12, pp. 1228–1242, 2017, ISSN: 0890-9369, 1549-5477, (Company: Cold Spring Harbor Laboratory Press Distributor: Cold Spring Harbor Laboratory Press Institution: Cold Spring Harbor Laboratory Press Label: Cold Spring Harbor Laboratory Press Publisher: Cold Spring Harbor Lab).
Abstract | Links | BibTeX | Tags: androgen receptor, ChIP-seq, CRPC, energy metabolism, nuclear receptor, steroid
@article{audet-walsh_nuclear_2017,
title = {Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer},
author = {Étienne Audet-Walsh and Catherine R Dufour and Tracey Yee and Fatima Z Zouanat and Ming Yan and Georges Kalloghlian and Mathieu Vernier and Maxime Caron and Guillaume Bourque and Eleonora Scarlata and Lucie Hamel and Fadi Brimo and Armen G Aprikian and Jacques Lapointe and Simone Chevalier and Vincent Giguère},
url = {http://genesdev.cshlp.org/content/31/12/1228},
doi = {10.1101/gad.299958.117},
issn = {0890-9369, 1549-5477},
year = {2017},
date = {2017-01-01},
urldate = {2021-05-18},
journal = {Genes & Development},
volume = {31},
number = {12},
pages = {1228--1242},
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.},
note = {Company: Cold Spring Harbor Laboratory Press
Distributor: Cold Spring Harbor Laboratory Press
Institution: Cold Spring Harbor Laboratory Press
Label: Cold Spring Harbor Laboratory Press
Publisher: Cold Spring Harbor Lab},
keywords = {androgen receptor, ChIP-seq, CRPC, energy metabolism, nuclear receptor, steroid},
pubstate = {published},
tppubtype = {article}
}
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.