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Differential effects on the translation of immune-related alternatively polyadenylated mRNAs in melanoma and T cells by eIF4A inhibitors

ABSTRACT: We explored the regulation of intronic polyadenylation (IPA) isoforms by silvestrol in melanoma and T lymphocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193966 | GEO | 2022/03/16

REPOSITORIES: GEO

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RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

Project description:The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of Silvestrol and related compounds. For example, eIF4A promotes T-ALL development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with Silvestrol has powerful therapeutic effects in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5'UTR sequences such as the 12-mer guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and Silvestrol-sensitive transcripts are a number of oncogenes, super-enhancer associated transcription factors, and epigenetic regulators. Hence, the 5'UTRs of selected cancer genes harbour a targetable requirement for the eIF4A RNA helicase. Comparison of ribosome-protected RNA for drug treated and DMSO treated KOPT-K1 cell, two replicates of ribosome-protected RNA sequencing and three replicates of RNA-seq.

2014-07-27 | E-GEOD-56887 | biostudies-arrayexpress

RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

2014-07-27 | GSE56887 | GEO

Ribosome profiling upon inhibition of eIF4A

Project description:Ribosome profiling of MDA-MB-231 cells treated with Silvestrol to monitor transcriptome wide, eIF4A-dependent changes in translation efficiency Translation efficiency (TE) of mRNAs dervied from ribosome footprints was monitored in the presence or absence of 25 nM Silvestrol, an inhibitor of eukaryotic translation initiation factor 4A (eIF4A). Transcripts with reduced TE in the presence of Silvestrol were compare to transcripts with reduced TE in the presence of INK128, a catalytic mTOR inhbitor.

2014-09-13 | E-GEOD-61375 | biostudies-arrayexpress

Cisplatin induces inefficiently translated short transcripts in long genes

Project description:We explored the regulation of intronic polyadenylation (IPA) by cisplatin, and its impact on the translatome.

2020-04-30 | GSE119978 | GEO

Compartment-specific and HuR-coordinated regulation of intronic polyadenylation isoforms by doxorubicin [total RNA-seq]

Project description:We explored the regulation of intronic polyadenylation (IPA) isoforms by doxorubicin and HuR in breast cancer cells.

2022-06-09 | GSE180849 | GEO

Compartment-specific and HuR-coordinated regulation of intronic polyadenylation isoforms by doxorubicin [3-seq]

Project description:We explored the regulation of intronic polyadenylation (IPA) isoforms by doxorubicin and HuR in several subcellular compartments.

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Differential regulation of alternatively polyadenylated isoforms

Project description:Alternative Cleavage and Polyadenylation (APA) plays a crucial role in the regulation of gene expression across eukaryotes. Although APA is extensively studied, its regulation within cellular compartments and its physiological impact remains largely enigmatic. Here, we employed a rigorous subcellular fractionation approach to compare APA profiles of cytoplasmic and nuclear RNA fractions from human cell lines. This comparison allowed us to extract APA isoforms that are subjected to differential regulation and provided us with a platform to interrogate the molecular regulatory pathways that shape the APA profiles in the subcellular locations. Subsequently, we depleted these cells of Dicer to compromise the miRNA biogenesis pathway to isolate the differentially regulated APA events that were regulated by miRNA.

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Targeting the eIF4A dependent translation of KRAS and other oncoproteins in pancreatic cancer

Project description:New and effective therapeutics are urgently needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). The eIF4A/DDX2 RNA helicase drives translation of mRNAs with highly structured 5’UTRs. The natural compound silvestrol and synthetic analogues are potent and selective inhibitors of eIF4A1/2 that show promising activity in models of hematological malignancies. Here, we show silvestrol analogues have nanomolar activity against PDAC cell lines and organoids in vitro. Moreover, we see single agent activity in the KRAS/p53 mouse PDAC model and also against PDAC xenografts and primary, patient derived PDAC tumors. These therapeutic effects occur at non-toxic dose levels. Transcriptome-wide ribosome profiling, analyses of protein and gene expression, and translation reporter studies reveal that eIF4A inhibitors block an oncogenic translation program in PDAC cells that includes G-quadruplex containing mRNAs such as KRAS, MYC, YAP1, MET, SMAD3, TGFβ and others. Together, our data indicate that pharmacological inhibition of eIF4A disrupts oncoprotein production and shows efficacy across several PDAC models.

2021-03-03 | GSE120159 | GEO

Ribosome profiling upon inhibition of eIF4A

Project description:Ribosome profiling of MDA-MB-231 cells treated with Silvestrol to monitor transcriptome wide, eIF4A-dependent changes in translation efficiency

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Compartment-specific and HuR-coordinated regulation of intronic polyadenylation isoforms by doxorubicin [CLIP-seq]

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2022-06-09 | GSE180848 | GEO

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