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EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer [RNA-seq]

ABSTRACT: Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE306580 | GEO | 2026/08/26

REPOSITORIES: GEO

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EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer

Project description:Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype.

2026-08-25 | GSE308826 | GEO

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer [ChIP-Seq]

2026-08-26 | GSE306733 | GEO

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer

Project description:EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer

| PRJNA1332765 | ENA

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer [ChIP-Seq]

Project description:EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer [ChIP-Seq]

| PRJNA1311992 | ENA

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer [RNA-seq]

Project description:EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer [RNA-seq]

| PRJNA1311348 | ENA

TTP-dependent mRNA decay in LPS-stimulated macrophages

2011-12-15 | GSE28880 | GEO

TTP mRNA targets identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts

Project description:Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that was identified through its rapid induction by mitogens in fibroblasts. Studies of TTP-deficient mice, and cells derived from them, showed that TTP could bind to certain AU-rich elements in mRNAs, leading to increases in the rates of mRNA deadenylation and destruction. Known physiological target mRNAs for TTP include tumor necrosis factor alpha (TNF), granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin 2 beta (IL2 beta). Here we used microarray analysis of RNA from wild-type and TTP-deficient fibroblast cell lines to identify transcripts with different decay rates, after serum stimulation and actinomycin D treatment. Of 250 mRNAs apparently stabilized in the absence of TTP, 23 contained conserved TTP binding sites; 10 of these were shown by secondary analyses to be stabilized. The most dramatically affected transcript encoded the protein Ier3, recently implicated in the physiological control of blood pressure. The Ier3 transcript contained several conserved TTP binding sites that could bind TTP directly, and conferred TTP sensitivity to the mRNA in cell transfection studies. These studies have identified several new, physiologically relevant TTP target transcripts in fibroblasts; these target mRNAs encode proteins from a variety of functional classes. Keywords: mRNA degradation, time course, knockout experiment

2006-10-17 | GSE5324 | GEO

Pre-mRNA fate decision by TTP safeguards the fidelity of the inflammatory response

Project description:Successful immune responses are dependent on a precisely controlled balance between transcription and mRNA degradation. mRNA decay is driven through RNA-binding proteins (RBP), yet it remains unclear, how and when an individual mRNA molecule is selected for degradation. We investigated this fundamental question by using the anti-inflammatory RBP tristetraprolin (TTP, also known as Zfp36) as a model. Here, we show that TTP determines the fate of its targets concomitantly with their synthesis by binding to the pre-mRNA in the nucleus. Furthermore, we provide evidence that TTP orchestrates the target destabilization via a hierarchical molecular assembly that culminates by the association of mature mRNA with the RNA degradation machinery in the cytoplasm. The early fate decision in the life cycle of a TTP target mRNA prevents the translation of inflammatory mediators, particularly cytokine mRNAs, and promotes efficient cessation of the immune response. Importantly, the TTP homolog ZFP36L1 displays similar characteristics, suggesting a conserved mode of action within the ZFP36 family of RBPs.

2025-01-27 | PXD046381 | Pride

TTP-dependent mRNA decay in LPS-stimulated macrophages

Project description:Controlled decay of cytokine and chemokine mRNAs restrains the time and amplitude of inflammatory responses. Tristetraprolin (TTP) binds to AU-rich elements in 3´ untranslated regions of mRNA and targets the bound mRNA for degradation. We have addressed here the function of TTP in balancing the macrophage activation state by a comprehensive analysis of TTP-dependent mRNA decay in LPS-stimulated macrophages from WT and TTP-deficient mice. We compared mRNA stability in LPS-treated BMDMs from WT and TTP-/- mice by microarray-based measurement of the remnant mRNA after transcriptional blockade with actinomycin D (act D). To increase the sensitivity of the mRNA decay profiling we inhibited the LPS-activated p38 MAPK with the specific inhibitor SB203580 since p38 MAPK negatively regulates the mRNA-destabilizing activity of TTP. LPS stimulation was for 3h before addition of act D. RNA was harvested at 0', 45' and 90' thereafter.

2011-12-15 | E-GEOD-28880 | biostudies-arrayexpress

Tristetraprolin (TTP) regulated splenic transcriptome in "TTPΔARE" mice

Project description:Tristetraprolin (TTP) binds to specific AU-rich elements in the 3'UTR of certain transcripts and regulates post-transcriptional gene expression by increasing the rate of mRNA turnover. Here, we generated a novel TTP mouse line (TTPΔARE) with a 136 base deletion in the 3'UTR AU-rich region of TTP mRNA, which resulted in a moderate increase in TTP protein expression in many tissues. In this study, we evaluated the effects of the moderate TTP overexpression on the overall pattern of gene expression in spleen, to investigate the effect of this mutation on mRNA targets of TTP under normal conditions. We utilized "TTPΔARE" (136 b deletion in the 3'UTR AU-rich region of Zfp36 mRNA) mice that overexpress TTP and compared the transcriptomic changes to the littermate "WT" mice. Spleen mRNA from four WT and four "TTPΔARE" mice were subjected to mRNA-Seq. All the animals used in this study were males between the ages of 8-12 weeks and were on a C57BL/6 background.

2019-01-19 | GSE65357 | GEO

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