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Remodeling oncogenic transcriptomes by small molecules targeting NONO

ABSTRACT: Remodeling oncogenic transcriptomes by small molecules targeting NONO

PROVIDER: PRJNA918613 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18301000_1.fastq.gz	Fastqsanger.gz
	SRR18301000_2.fastq.gz	Fastqsanger.gz
	SRR18301001_1.fastq.gz	Fastqsanger.gz
	SRR18301001_2.fastq.gz	Fastqsanger.gz
	SRR18301002_1.fastq.gz	Fastqsanger.gz

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Remodeling oncogenic transcriptomes by small molecules targeting NONO

Project description:A large swath of the human proteome is dedicated to mRNA homeostasis, but most RNA-binding proteins lack chemical probes. Here, we report the discovery through phenotypic screening of electrophilic small molecules that swiftly (within 4 h) and stereospecifically decrease transcripts encoding the androgen receptor (AR) and its major V7 splice variant in human prostate cancer cells. We show by chemical proteomics that these compounds covalently engage cysteine-145 of the RNA-binding protein NONO. Broader profiling revealed that covalent NONO ligands suppress a discrete set of transcripts and proteins, including multiple oncogenic transcription factors, and impair the proliferation of cancer cells. These effects were not observed following genetic disruption of NONO, which instead blocked ligand activity. The covalent ligands promote accumulation of NONO in nuclear foci and at the first 5’ splice site of immature transcripts, pointing to a trapping mechanism that may prevent the compensatory action of the paralogous proteins PSPC1 and SFPQ, which were found to increase in cancer cells following genetic or chemical perturbation of NONO. These findings, taken together, designate NONO as a druggable RNA-binding protein that can be co-opted by covalent small molecules to suppress pro-tumorigenic transcriptional networks.

2024-01-26 | PXD039283 | Pride

Remodeling of oncogenic transcriptomes by small molecules targeting the RNA-binding protein NONO

Project description:A large swath of the human proteome is dedicated to mRNA homeostasis, but most RNA-binding proteins lack chemical probes1,2. Here, we report the discovery through phenotypic screening of electrophilic small molecules that swiftly (within 4 h) and stereospecifically decrease transcripts encoding the androgen receptor (AR) and its major V7 splice variant in human prostate cancer cells. We show by chemical proteomics that these compounds covalently engage cysteine-145 on the RNA-binding protein NONO. Broader profiling revealed that covalent NONO ligands suppress a discrete set of transcripts and proteins, including multiple oncogenic transcription factors, and impair the proliferation of cancer cells. These effects were not observed following genetic disruption of NONO, which instead blocked ligand activity. The covalent ligands promote accumulation of NONO in nuclear foci and at the first 5’ splice site of immature transcripts, pointing to a trapping mechanism that may prevent compensatory action by the related protein PSPC1, which was found to increase in cancer cells following genetic or chemical perturbation of NONO. These findings, taken together, designate NONO as a druggable RNA-binding protein that can be co-opted by covalent small molecules to suppress pro-tumorigenic transcriptional networks.

2024-01-26 | PXD032087 | Pride

Remodeling of oncogenic transcriptomes by small-molecules targeting the RNA-binding protein NONO

Project description:A large swath of the human proteome is dedicated to RNA homeostasis, but most RNA-binding proteins lack chemical probes1,2. Here, phenotypic screening led to the discovery of electrophilic small molecules that swiftly (within 4 h) and stereospecifically decrease transcripts encoding the androgen receptor (AR) and its major V7 splice variant in human prostate cancer cells. We show by chemical proteomics that these compounds covalently engage cysteine-145 on the RNA-binding protein NONO. Transcriptomics and proteomics profiling revealed that covalent NONO ligands suppress a discrete set of transcripts and proteins, including multiple oncogenic transcription factors, and impair the proliferation of cancer cells. These effects were not observed following genetic disruption of NONO, which instead blocked ligand activity. The covalent ligands promote accumulation of NONO in nuclear foci and at the first 5 splice site of immature transcripts, pointing to a trapping mechanism that may prevent compensatory action by the related protein PSPC1, which was found to increase in cancer cells following genetic or chemical perturbation of NONO. These findings, taken together, designate NONO as a druggable RNA-binding protein that can be co-opted by covalent small molecules to suppress pro-tumorigenic transcriptional networks.

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Remodeling of oncogenic transcriptomes by small-molecules targeting the RNA-binding protein NONO

Project description:Remodeling of oncogenic transcriptomes by small-molecules targeting the RNA-binding protein NONO

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Remodeling oncogenic transcriptomes by small molecules targeting NONO

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

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NONO mutations cause syndromic intellectual disability and inhibitory synaptic defects

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NONO mutations cause syndromic intellectual disability and inhibitory synaptic defects

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Project description:siRNA knockdown of NONO mRNA followed by RNA-seq was carried out in the KELLY neuroblasotma cell line. In order to determine potential regulatory targets of NONO protein, we performed differential expression analysis. To identify the RNA targets of NONO in neuroblastoma, we carried out PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) using an antibody recognising NONO protein.

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Second generation molecules targeting the oncogenic signal mediator, RHOA in gastric cancer

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