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The RNA helicase DHX30 coordinates cytoplasmic translation and mitochondrial function contributing to cancer cell survival

ABSTRACT: Total RNA profiling of control and DHX30-silenced HCT116 cells, either with no treatment and after Nutlin-3 treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154065 | GEO | 2021/09/15

REPOSITORIES: GEO

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p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30.

Project description:Activation of p53 by the small molecule Nutlin can result in a combination of cell cycle arrest and apoptosis. The relative strength of these events is difficult to predict, leaving uncertainty as to the therapeutic benefits of Nutlin. Here, we report a new translation control mechanism shaping p53-dependent apoptosis. We performed polysomal profiling in the cell lines SJSA1 and HCT116, of which only the first undergoes robust cell death in response to p53 activation by Nutlin. We establish Nutlin-induced apoptosis in SJSA1 cells to be associated with a set of translationally enhanced mRNAs carrying a newly identified 3’UTR motif which we labeled CG-motif. We identified PCBP2 and DHX30 as interactor proteins of the CG-motif that are more abundant in HCT116 cells compared to SJSA1. The binding of DHX30 to the CG-motif detected in HCT116 cells was shown to be dependent on PCBP2. Interestingly, DHX30 depletion enhances polysome association of CG-motif mRNAs in HCT116 cells, shifting their outcome towards apoptosis. In U2OS, an osteosarcoma-derived cell line that unlike SJSA1 undergoes persistent cell cycle arrest in response to Nutlin, DHX30 is highly expressed and its depletion enhances the expression of CG-motif mRNAs.

2020-03-30 | GSE95024 | GEO

The RNA helicase DHX30 coordinates cytoplasmic translation and mitochondrial function contributing to cancer cell survival

Project description:The RNA helicase DHX30 coordinates cytoplasmic translation and mitochondrial function contributing to cancer cell survival

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DHX30 Coordinates Cytoplasmic Translation and Mitochondrial Function Contributing to Cancer Cell Survival.

Project description:DHX30 was recently implicated in the translation control of mRNAs involved in p53-dependent apoptosis. Here, we show that DHX30 exhibits a more general function by integrating the activities of its cytoplasmic isoform and of the more abundant mitochondrial one. The depletion of both DHX30 isoforms in HCT116 cells leads to constitutive changes in polysome-associated mRNAs, enhancing the translation of mRNAs coding for cytoplasmic ribosomal proteins while reducing the translational efficiency of the nuclear-encoded mitoribosome mRNAs. Furthermore, the depletion of both DHX30 isoforms leads to higher global translation but slower proliferation and lower mitochondrial energy metabolism. Isoform-specific silencing supports a role for cytoplasmic DHX30 in modulating global translation. The impact on translation and proliferation was confirmed in U2OS and MCF7 cells. Exploiting RIP, eCLIP, and gene expression data, we identified fourteen mitoribosome transcripts we propose as direct DHX30 targets that can be used to explore the prognostic value of this mechanism in cancer. We propose that DHX30 contributes to cell homeostasis by coordinating ribosome biogenesis, global translation, and mitochondrial metabolism. Targeting DHX30 could, thus, expose a vulnerability in cancer cells.

| S-EPMC8430983 | biostudies-literature

Global analysis of p53-regulated transcription reveals its direct targets and unexpected regulatory mechanisms (microarray)

Project description:HCT116 microarray done 12 hours after treatment with DMSO (control) or Nutlin

2014-05-15 | GSE53965 | GEO

Global analysis of p53-regulated transcription reveals its direct targets and unexpected regulatory mechanisms (GRO-Seq)

Project description:GRO-seq of HCT116 cells treated with Nutlin to activate p53 HCT116 cells were treated with Nutlin or DMSO for 1 hour

2014-05-15 | E-GEOD-53964 | biostudies-arrayexpress

HCT116 cells isogenic for p53 expression upon treatment with actinomycin D and nutlin-3

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HCT116 cells isogenic for p53 expression upon treatment with actinomycin D and nutlin-3

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Global analysis of p53-regulated transcription reveals its direct targets and unexpected regulatory mechanisms (GRO-Seq)

Project description:GRO-seq of HCT116 cells treated with Nutlin to activate p53

2014-05-15 | GSE53964 | GEO

Global analysis of p53-regulated transcription reveals its direct targets and unexpected regulatory mechanisms (microarray)

Project description:HCT116 microarray done 12 hours after treatment with DMSO (control) or Nutlin Total RNA from HCT116 cells was harvested with an RNeasy kit (Qiagen) and analyzed on Affymetrix HuGene 1.0 ST arrays following the manufacturer’s instructions. Microarray data were processed using Partek Genomics Suite 6.6. Anova was used to call differentially expressed genes for which any isoform showed a fold change > |+/-1.5| with FDR <0.05. There were 362 genes called as upregulated and 367 genes as downregulated.

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