Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells.

mTOR is a serine/threonine kinase that controls prostate cancer (PCa) cell growth in part by regulating gene programs associated with metabolic and cell proliferation pathways. mTOR-mediated control of gene expression can be achieved via phosphorylation of transcription factors, leading to changes in their cellular localization and activities. mTOR also directly associates with chromatin in complex with transcriptional regulators, including the androgen receptor (AR). Nuclear mTOR (nmTOR) has been previously shown to act as a transcriptional integrator of the androgen signaling pathway in association with the chromatin remodeling machinery, AR, and FOXA1. However, the contribution of cytoplasmic mTOR (cmTOR) and nmTOR and the role played by FOXA1 in this process remains to be explored. Herein, we engineered cells expressing mTOR tagged with nuclear localization and export signals dictating mTOR localization. Transcriptome profiling in AR-positive PCa cells revealed that nmTOR generally downregulates a subset of the androgen response pathway independently of its kinase activity, while cmTOR upregulates a cell cycle-related gene signature in a kinase-dependent manner. Biochemical and genome-wide transcriptomic analyses demonstrate that nmTOR functionally interacts with AR and FOXA1. Ablation of FOXA1 reprograms the nmTOR cistrome and transcriptome of androgen responsive PCa cells. This works highlights a transcriptional regulatory pathway in which direct interactions between nmTOR, AR and FOXA1 dictate a combinatorial role for these factors in the control of specific gene programs in PCa cells. Implications: The finding that canonical and nuclear mTOR signaling pathways control distinct gene programs opens therapeutic opportunities to modulate mTOR activity in PCa cells.