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MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [ChIP-Seq]

ABSTRACT: MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [ChIP-Seq]

PROVIDER: PRJNA1035058 | ENA |

REPOSITORIES: ENA

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MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [ChIP-Seq]

Project description:Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR) which is a pivotal regulator of cellular metabolism, and epigenetic modifications remains poorly understood. We thus explored the impact of modulating mTOR signaling on histone methylation, a well-known epigenetic modification. Our results show that constitutive mTORC1 activation caused by abrogation of TSC2 increases H3K27me3 but not H3K4me3 or H3K9me3, via 4E-BPs-mediated induction of EZH2 protein levels. Surprisingly, mTOR inhibition also induced H3K27me3 independently of TSC2. This coincided with reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the ability of mTOR inhibitors to induce H3K27me3 influences their anti-proliferative effects.

2023-11-02 | GSE246887 | GEO

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [RNA-Seq]

2023-11-02 | GSE246886 | GEO

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors

Project description:MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors

| PRJNA1035055 | ENA

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [RNA-Seq]

Project description:MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [RNA-Seq]

| PRJNA1035059 | ENA

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors

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

2023-11-02 | GSE246889 | GEO

Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

Project description:Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

| PRJNA554692 | ENA

mTOR

Project description:mTOR

| PRJEB9498 | ENA

Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

Project description:The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and an attractive anti-cancer target that integrates diverse signals to control cell proliferation. Previous studies using mTOR inhibitors have shown that mTOR targeting suppresses gene expression and cell proliferation. To date, however, mTOR targeted therapies in cancer have seen very limited efficacy, and one key issue is related to the development of evasive resistance. In this manuscript, through the use of a gene targeting mouse model, we have found that inducible deletion of mTOR in hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to the mTOR loss, mTOR-/- HSCs increase chromatin accessibility and activate global gene expression, contrary to the effects of short-term inhibition by mTOR inhibitors. Mechanistically, such genomic changes are due to a rewiring and adaptive activation of the ERK/MNK/eIF4E signaling pathway that enhances the protein translation of RNA polymerase II (RNAP II), which in turn leads to increased c-Myc gene expression, allowing the HSCs to thrive despite loss of a functional mTOR pathway. This adaptive mechanism can also be utilized by leukemia cells undergoing long-term mTOR inhibitor treatment to confer resistance to mTOR drug targeting. The resistance can then be counteracted by MNK, CDK9, or c-Myc inhibition. These results provide new insights into the physiological role of mTOR in mammalian stem cell regulation and implicate a novel mechanism of evasive resistance in the context of mTOR targeting.

2020-12-24 | GSE134316 | GEO

SUM52PE treated with PI3K-mTOR inhibitors

Project description:SUM52PE treated with PI3K-mTOR inhibitors

| PRJNA509669 | ENA

Selective Inhibitors of mTORC1 Activate 4EBP1 and Suppress Tumor Growth

Project description:The clinical benefit of current mTOR inhibitors is limited, perhaps reflecting their intrinsic pharmacological profiles. Rapamycin analogs selectively inhibit mTORC1, but fail to suppress phosphorylation of the mTORC1 substrate 4EBP1, a translational repressor that is a key driver of oncogenic mTORC1 signaling. mTOR kinase active-site inhibitors fully suppress mTORC1 and phosphorylation of its substrates, but are active against mTORC2 and additional kinases, potentially contributing to tolerability limitations. The prototype bi-steric inhibitor RapaLink-1 exploits the selective mTORC1 interactions of rapamycin and the broad mTOR kinase inhibitory effects of an active-site inhibitor, through covalent linkage of the two pharmacophores to achieve complete mTORC1/2 inhibition. We demonstrate that the anti-proliferative activity of RapaLink-1 is dependent upon mTORC1 and suppression of 4EBP1 phosphorylation. Using a rational design strategy, we tuned the affinities of the rapamycin core and ATP-mimetic moieties to create novel bi-steric inhibitors with enhanced mTORC1 selectivity and potency against 4EBP1 phosphorylation. mTORC1-selective bi-steric compounds produced durable inhibition of 4EBP1 phosphorylation in vitro and in vivo, and drove tumor regressions at well-tolerated doses in xenograft models of breast cancer.

2021-04-05 | GSE138417 | GEO

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