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

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

PROVIDER: PRJNA934335 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23445600_1.fastq.gz	Fastqsanger.gz
	SRR23445600_2.fastq.gz	Fastqsanger.gz
	SRR23445601_1.fastq.gz	Fastqsanger.gz
	SRR23445601_2.fastq.gz	Fastqsanger.gz
	SRR23445602_1.fastq.gz	Fastqsanger.gz

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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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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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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.

2023-07-19 | GSE225205 | GEO

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

2023-10-11 | GSE225196 | GEO

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

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

2023-07-23 | GSE225207 | GEO

Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer elicits improved anti-tumor efficacy and apoptosis

Project description:Both the PI3K/AKT/mTOR and androgen receptor (AR) signaling pathways play essential roles in prostate cancer. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and apoptosis induction, and observed the strongest effects in androgen-sensitive prostate cancer models. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, with most pronounced effects of the pan-PI3K inhibitor copanlisib. Transcriptomic analysis performed in the androgen-sensitive VCaP cell line revealed that gene expression was more affected by the co-treatment with darolutamide and copanlisib, compared to single agents. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs was observed. The combination treatment also markedly induced DNA damage. An in vivo efficacy study performed using LuCaP 35, an androgen-sensitive patient-derived prostate cancer model, indicated superior efficacy after combined treatment with copanlisib and darolutamide. Immunohistochemistry analysis of treated tumors furthermore showed increased apoptosis. Altogether these data demonstrate that blocking the PI3K/AKT/mTOR and AR pathways with potent inhibitors has superior anti-tumor efficacy and induces apoptosis in androgen-sensitive prostate cancer models.

2024-01-22 | GSE245454 | GEO

Canonical and non-canonical regulatory roles of androgen receptor variant 7 in prostate cancer

Project description:The androgen receptor splice variant 7 (AR-V7) lacks the ligand-binding domain; is detected with increased frequency in advanced prostate cancer and is postulated to be one crucial mechanism for disease progression and therapeutic resistance to androgen deprivation in castration–resistant prostate cancer (CRPC). Targeting AR-V7 or unique downstream targets could provide novel therapeutic approaches for CRPC. Here, we report that, independent of ligand, AR-V7 binds not only to the androgen-responsive element (ARE) sites inducing canonical AR signaling but also to non-canonical target sites where ligand-stimulated full-length AR (AR-FL) does not bind. These AR-V7 “solo” binding sites are mainly found at gene promoters and are co-occupied by a zinc-finger transcription factor ZFX and the co-activator BRD4, both of which physically interact with AR-V7. Consequently, AR-V7 not only recapitulates AR-FL action without androgen but uniquely regulates transcripts correlating with AR-V7 expression in the TCGA prostate cancer cohort. Mechanistically, ZFX appears to function as a pioneer factor for AR-V7 at solo-binding sites and BRD4 inhibitors but not anti-androgens suppress AR-V7 action at solo-binding sites as well as AR-V7-dependent growth. Additionally, knockdown of ZFX, or two downstream targets uniquely co-activated by AR-V7 (ZNF32 and FZD6), also suppressed growth of AR-V7-dependent CRPC cells. AR-V7 directly activated genes differentiate tumor from normal prostate tissues and predict poor prognosis in patients. Thus AR-V7 has both canonical and non-canonical regulatory functions in CRPC, which may provide new therapeutic avenues.

2018-10-02 | GSE94013 | GEO

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

Transcriptome profiles of canonical MED19 LNCaP and control LNCaP cells cultured under androgen deprivation with vehicle or R1881 treatment

Project description:We report the application of RNA sequencing to uncover the process through which sustained overexpression of the canonical MED19 isoform in androgen-dependent LNCaP cells enhances growth under conditions of androgen deprivation. We identified the canonical MED19 transcriptome by comparing control LNCaP cells with those expressing canonical MED19. This research offers significant understanding of the mechanism by which prostate cancer cells grow under low androgen conditions, emphasizing the key role of the canonical MED19 isoform in this process.

2023-07-06 | GSE236441 | GEO

Redefinition of Human Androgen Responsive Elements [FOX_ChIP_exo]

Project description:The androgen receptor (AR) mediates the action of androgens by binding to androgen-responsive elements (AREs) and subsequently regulating target genes involved in prostate carcinogenesis. The precise locations, true nature, and functional roles of AREs in human prostate cancer are still unknown. Here we redefine AREs by motif-resolution AR chromatin immunoprecipitation-exonuclease (ChIP-exo) assay in human prostate cancer cells and tumors. Surprisingly, we find that, in addition to canonical full-length AREs and half-site-like AREs, a significant portion of the four redefined ARE categories comprises non-canonical full-length AREs. The redefined AREs in enhanced AR binding regions in prostate tumors versus paired non-malignant adjacent tissues regulate a prostate cancer-relevant gene network not only centered on AR, but more interestingly, on novel AR target genes mTOR, BIRC5 and BCL2L1 involved in prostate cancer cell growth and survival. The precise redefinition of AREs has important implications for understanding how AR contributes to prostate carcinogenesis. FOXA1 ChIP-exo

2015-01-01 | E-GEOD-43678 | biostudies-arrayexpress

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