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

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

PROVIDER: PRJNA362588 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5189294.fastq.gz	Fastqsanger.gz
	SRR5189295.fastq.gz	Fastqsanger.gz
	SRR5189296.fastq.gz	Fastqsanger.gz
	SRR5189297.fastq.gz	Fastqsanger.gz
	SRR5189298.fastq.gz	Fastqsanger.gz

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Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer progression [ChIP-seq]

Project description:Whether the nuclear fraction of mTOR plays a role in prostate cancer (PCa) and can participate in direct transcriptional crosstalk with the androgen receptor (AR) is as yet unknown. The intersection of gene expression, DNA binding-events, and metabolic studies uncovered the existence of a nuclear mTOR-AR transcriptional axis dictating the metabolic rewiring and nutrient usage of PCa cells. In human clinical specimens, nuclear localization of mTOR was significantly associated with metastasis and castration-resistant PCa (CRPC), correlating with a sustained metabolic gene program governed by mTOR in that context. This study thus uncovers an unexpected function of mTOR and underscores a paradigm shift from AR to mTOR as being the master transcriptional regulator of cell metabolism during PCa progression. We performed ChIP-seq of mTOR to study its role in LNCaP cells with or without androgen stimulation. The study was done twice independently; processed data are shown as a pool of either vehicle-treated samples or R1881-treated samples.

2017-07-18 | GSE93845 | GEO

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer progression [array]

Project description:Whether the nuclear fraction of mTOR plays a role in prostate cancer (PCa) and can participate in direct transcriptional crosstalk with the androgen receptor (AR) is as yet unknown. The intersection of gene expression, DNA binding-events, and metabolic studies uncovered the existence of a nuclear mTOR-AR transcriptional axis dictating the metabolic rewiring and nutrient usage of PCa cells. In human clinical specimens, nuclear localization of mTOR was significantly associated with metastasis and castration-resistant PCa (CRPC), correlating with a sustained metabolic gene program governed by mTOR in that context. This study thus uncovers an unexpected function of mTOR and underscores a paradigm shift from AR to mTOR as being the master transcriptional regulator of cell metabolism during PCa progression. We used microarrays to investigate the role of nuclear mTOR in prostate cancer cell transcriptional regulation by androgens in LNCaP cells.

2017-07-18 | GSE93603 | GEO

Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells [RNAseq_mTOR]

Project description: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.

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Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells [ChIP-Seq]

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

Project description: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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The Prostate Cancer mTOR Chromatin-Bound Interactome

Project description:Growing studies support a direct role for nuclear mTOR in gene regulation and chromatin structure. Still, the scarcity of known chromatin-bound mTOR partners limits our understanding of how nuclear mTOR controls transcription. Herein, we comprehensively mapped the mTOR chromatin-bound interactome in four cellular models of prostate cancer (PCa) identifying a conserved 67-protein interaction network enriched for epigenetic and transcription factors as well as SUMOylation machinery in both androgen-dependent and -independent cells. Notably, SUMO2/3 and nuclear pore protein NUP210 are among the strongest interactors while the androgen receptor (AR) is the dominant androgen-inducible mTOR partner. Further investigation showed that NUP210 facilitates mTOR nuclear trafficking, that mTOR, AR and NuRD act as a functional transcriptional complex, and that androgens dictate mTOR-SUMO2/3 promoter-enhancer specificity. This work identifies a vast network of mTOR-associated nuclear complexes advocating novel molecular strategies to modulate mTOR-dependent gene regulation with evident implications for PCa and other diseases.

2022-04-01 | PXD026101 | Pride

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

Project description:Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells

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Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells [RNAseq_mTOR]

Project description:Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells [RNAseq_mTOR]

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-07-18 | GSE93846 | GEO

Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells [ChIP-Seq]

Project description:Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells [ChIP-Seq]

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