Remodeling oncogenic transcriptomes by small molecules targeting NONO
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA918613 | ENA |
REPOSITORIES: ENA
Dataset's files
| 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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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
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
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.
2023-03-03 | GSE198212 | GEO
Project description:Remodeling of oncogenic transcriptomes by small-molecules targeting the RNA-binding protein NONO
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Project description:Much of the human proteome is involved in mRNA homeostasis, but most RNA-binding proteins lack chemical probes. Here we identify electrophilic small molecules that rapidly and stereoselectively decrease the expression of transcripts encoding the androgen receptor and its splice variants in prostate cancer cells. We show by chemical proteomics that the compounds engage C145 of the RNA-binding protein NONO. Broader profiling revealed that covalent NONO ligands suppress an array of cancer-relevant genes and impair cancer cell proliferation. Surprisingly, these effects were not observed in cells genetically disrupted for NONO, which were instead resistant to NONO ligands. Reintroduction of wild-type NONO, but not a C145S mutant, restored ligand sensitivity in NONO-disrupted cells. The ligands promoted NONO accumulation in nuclear foci and stabilized NONO-RNA interactions, supporting a trapping mechanism that may prevent compensatory action of paralog proteins PSPC1 and SFPQ. These findings show that NONO can be co-opted by covalent small molecules to suppress protumorigenic transcriptional networks.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-21 | GSE222217 | GEO
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2895 | biostudies-arrayexpress
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2894 | biostudies-arrayexpress
Project description:To investigate the RNA binding proterties of NONO and NONO-delta-ER in testis; we collected adult NONO and NONO-delta-ER mice testis We then performed eCLIP-seq respectively and convey subsequent bioinformatic analysis.
2024-08-08 | GSE263329 | GEO
Project description:Second generation molecules targeting the oncogenic signal mediator, RHOA in gastric cancer
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