Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

作者：Audet Walsh Etienne; 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; Giguere Vincent^*

来源：Genes & Development, 2017, 31(12): 1228-1242.

DOI：10.1101/gad.299958.117

• androgen receptor
• CRPC
• energy metabolism
• nuclear receptor
• steroid
• ChIP-seq

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.

• 出版日期2017-6-15