Remodeling oncogenic transcriptomes by small molecules targeting NONO.
Stefan G Kathman,
Seong Joo Koo,
Garrett L Lindsey,
Hsuan-Lin Her,
Steven M Blue,
Haoxin Li,
Steffen Jaensch,
Jarrett R Remsberg,
Kay Ahn,
Gene W Yeo,
Brahma Ghosh,
Benjamin F Cravatt
Nature chemical biology
· 2023
· Vol. 19
(7)
· pp. 825-836
Abstract
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.
Publication Types
["Journal Article", "Research Support, N.I.H., Extramural", "Research Support, Non-U.S. Gov't"]
Keywords
MeSH Terms
["Male", "Humans", "DNA-Binding Proteins", "Transcriptome", "RNA-Binding Proteins", "RNA"]
Funding
R01 CA238249
NCI NIH HHS
(United States)
R35 CA231991
NCI NIH HHS
(United States)
R01 HG004659
NHGRI NIH HHS
(United States)
U41 HG009889
NHGRI NIH HHS
(United States)
R01 HL137223
NHLBI NIH HHS
(United States)
F32 CA228436
NCI NIH HHS
(United States)
U01 HG009417
NHGRI NIH HHS
(United States)
Linked Datasets (3)
Transcriptome changes in 22Rv1 cells with a double knockout or over expression of C145S, Empty vector, or Wild type NONO.
Homo sapiens90 data files
| File | Type | Size |
|---|---|---|
| C145S10R-1_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| C145S10R-1_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| C145S10R-2_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| C145S10R-2_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| C145S10R-3_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| C145S10R-3_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| C145S10S-1_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| C145S10S-1_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| C145S10S-2_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| C145S10S-2_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| C145S10S-3_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| C145S10S-3_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| C145SD-1_R1_001.fastq.gz | RNA-Seq | 2.8 GB |
| C145SD-1_R1_001.fastq.gz | RNA-Seq | 2.8 GB |
| C145SD-2_R1_001.fastq.gz | RNA-Seq | 2.2 GB |
| C145SD-2_R1_001.fastq.gz | RNA-Seq | 2.2 GB |
| C145SD-3_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| C145SD-3_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| EV10R-1_R1_001.fastq.gz | RNA-Seq | 1.9 GB |
| EV10R-1_R1_001.fastq.gz | RNA-Seq | 1.9 GB |
| EV10R-2_R1_001.fastq.gz | RNA-Seq | 1.8 GB |
| EV10R-2_R1_001.fastq.gz | RNA-Seq | 1.8 GB |
| EV10R-3_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| EV10R-3_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| EV10S-1_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| EV10S-1_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| EV10S-2_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| EV10S-2_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| EV10S-3_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| EV10S-3_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| EVD-1_R1_001.fastq.gz | RNA-Seq | 2.0 GB |
| EVD-1_R1_001.fastq.gz | RNA-Seq | 2.0 GB |
| EVD-2_R1_001.fastq.gz | RNA-Seq | 2.0 GB |
| EVD-2_R1_001.fastq.gz | RNA-Seq | 2.0 GB |
| EVD-3_R1_001.fastq.gz | RNA-Seq | 2.2 GB |
| EVD-3_R1_001.fastq.gz | RNA-Seq | 2.2 GB |
| sgControl-sgCtrl1_R1_001.fastq.gz | RNA-Seq | 3.0 GB |
| sgControl-sgCtrl1_R1_001.fastq.gz | RNA-Seq | 3.0 GB |
| sgControl-sgCtrl2_R1_001.fastq.gz | RNA-Seq | 3.3 GB |
| sgControl-sgCtrl2_R1_001.fastq.gz | RNA-Seq | 3.3 GB |
| sgControl-sgCtrl3_R1_001.fastq.gz | RNA-Seq | 3.1 GB |
| sgControl-sgCtrl3_R1_001.fastq.gz | RNA-Seq | 3.1 GB |
| sgControl-sgPSPC11_R1_001.fastq.gz | RNA-Seq | 3.1 GB |
| sgControl-sgPSPC11_R1_001.fastq.gz | RNA-Seq | 3.1 GB |
| sgControl-sgPSPC12_R1_001.fastq.gz | RNA-Seq | 2.9 GB |
| sgControl-sgPSPC12_R1_001.fastq.gz | RNA-Seq | 2.9 GB |
| sgControl-sgPSPC13_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| sgControl-sgPSPC13_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| sgControl-sgSFPQ12_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| sgControl-sgSFPQ12_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| sgControl-sgSFPQ1_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| sgControl-sgSFPQ1_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| sgControl-sgSFPQ3_R1_001.fastq.gz | RNA-Seq | 2.9 GB |
| sgControl-sgSFPQ3_R1_001.fastq.gz | RNA-Seq | 2.9 GB |
| sgNONO-sgCtrl1_R1_001.fastq.gz | RNA-Seq | 3.3 GB |
| sgNONO-sgCtrl1_R1_001.fastq.gz | RNA-Seq | 3.3 GB |
| sgNONO-sgCtrl2_R1_001.fastq.gz | RNA-Seq | 3.0 GB |
| sgNONO-sgCtrl2_R1_001.fastq.gz | RNA-Seq | 3.0 GB |
| sgNONO-sgCtrl3_R1_001.fastq.gz | RNA-Seq | 2.9 GB |
| sgNONO-sgCtrl3_R1_001.fastq.gz | RNA-Seq | 2.9 GB |
| sgNONO-sgPSPC11_R1_001.fastq.gz | RNA-Seq | 3.0 GB |
| sgNONO-sgPSPC11_R1_001.fastq.gz | RNA-Seq | 3.0 GB |
| sgNONO-sgPSPC12_R1_001.fastq.gz | RNA-Seq | 2.9 GB |
| sgNONO-sgPSPC12_R1_001.fastq.gz | RNA-Seq | 2.9 GB |
| sgNONO-sgPSPC13_R1_001.fastq.gz | RNA-Seq | 2.8 GB |
| sgNONO-sgPSPC13_R1_001.fastq.gz | RNA-Seq | 2.8 GB |
| sgNONO-sgSFPQ1_R1_001.fastq.gz | RNA-Seq | 3.1 GB |
| sgNONO-sgSFPQ1_R1_001.fastq.gz | RNA-Seq | 3.1 GB |
| sgNONO-sgSFPQ2_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| sgNONO-sgSFPQ2_R1_001.fastq.gz | RNA-Seq | 2.7 GB |
| sgNONO-sgSFPQ3_R1_001.fastq.gz | RNA-Seq | 3.0 GB |
| sgNONO-sgSFPQ3_R1_001.fastq.gz | RNA-Seq | 3.0 GB |
| WT10R-1_R1_001.fastq.gz | RNA-Seq | 2.2 GB |
| WT10R-1_R1_001.fastq.gz | RNA-Seq | 2.2 GB |
| WT10R-2_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| WT10R-2_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| WT10R-3_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| WT10R-3_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| WT10S-1_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| WT10S-1_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| WT10S-2_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| WT10S-2_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| WT10S-3_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| WT10S-3_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| WTD-1_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| WTD-1_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| WTD-2_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| WTD-2_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| WTD-3_R1_001.fastq.gz | RNA-Seq | 2.1 GB |
| WTD-3_R1_001.fastq.gz | RNA-Seq | 2.1 GB |
Remodeling oncogenic transcriptomes by small molecules targeting NONO
Homo sapiensTranscriptome changes in 22Rv1 and MCF7 cells after treatment with NONO ligands and controls
Homo sapiens72 data files
| File | Type | Size |
|---|---|---|
| Ctrl210R1_R1_001.fastq.gz | RNA-Seq | 3.2 GB |
| Ctrl210R1_R1_001.fastq.gz | RNA-Seq | 3.2 GB |
| Ctrl210R2_R1_001.fastq.gz | RNA-Seq | 3.8 GB |
| Ctrl210R2_R1_001.fastq.gz | RNA-Seq | 3.8 GB |
| Ctrl210R3_R1_001.fastq.gz | RNA-Seq | 3.5 GB |
| Ctrl210R3_R1_001.fastq.gz | RNA-Seq | 3.5 GB |
| Ctrl210S1_R1_001.fastq.gz | RNA-Seq | 4.7 GB |
| Ctrl210S1_R1_001.fastq.gz | RNA-Seq | 4.7 GB |
| Ctrl210S2_R1_001.fastq.gz | RNA-Seq | 3.4 GB |
| Ctrl210S2_R1_001.fastq.gz | RNA-Seq | 3.4 GB |
| Ctrl210S3_R1_001.fastq.gz | RNA-Seq | 3.9 GB |
| Ctrl210S3_R1_001.fastq.gz | RNA-Seq | 3.9 GB |
| Ctrl2DMSO1_R1_001.fastq.gz | RNA-Seq | 2.1 GB |
| Ctrl2DMSO1_R1_001.fastq.gz | RNA-Seq | 2.1 GB |
| Ctrl2DMSO2_R1_001.fastq.gz | RNA-Seq | 3.1 GB |
| Ctrl2DMSO2_R1_001.fastq.gz | RNA-Seq | 3.1 GB |
| Ctrl2DMSO3_R1_001.fastq.gz | RNA-Seq | 3.2 GB |
| Ctrl2DMSO3_R1_001.fastq.gz | RNA-Seq | 3.2 GB |
| KO310R1_R1_001.fastq.gz | RNA-Seq | 4.2 GB |
| KO310R1_R1_001.fastq.gz | RNA-Seq | 4.2 GB |
| KO310R2_R1_001.fastq.gz | RNA-Seq | 4.4 GB |
| KO310R2_R1_001.fastq.gz | RNA-Seq | 4.4 GB |
| KO310R3_R1_001.fastq.gz | RNA-Seq | 4.7 GB |
| KO310R3_R1_001.fastq.gz | RNA-Seq | 4.7 GB |
| KO310S1_R1_001.fastq.gz | RNA-Seq | 4.3 GB |
| KO310S1_R1_001.fastq.gz | RNA-Seq | 4.3 GB |
| KO310S2_R1_001.fastq.gz | RNA-Seq | 3.5 GB |
| KO310S2_R1_001.fastq.gz | RNA-Seq | 3.5 GB |
| KO310S3_R1_001.fastq.gz | RNA-Seq | 3.5 GB |
| KO3DMSO1_R1_001.fastq.gz | RNA-Seq | 6.4 GB |
| KO3DMSO1_R1_001.fastq.gz | RNA-Seq | 6.4 GB |
| KO3DMSO2_R1_001.fastq.gz | RNA-Seq | 3.2 GB |
| KO3DMSO2_R1_001.fastq.gz | RNA-Seq | 3.2 GB |
| KO3DMSO3_R1_001.fastq.gz | RNA-Seq | 4.1 GB |
| KO3DMSO3_R1_001.fastq.gz | RNA-Seq | 4.1 GB |
| SK-C1-10R-1_R1_001.fastq.gz | RNA-Seq | 8.5 GB |
| SK-C1-10R-1_R1_001.fastq.gz | RNA-Seq | 8.5 GB |
| SK-C1-10R-2_R1_001.fastq.gz | RNA-Seq | 11.5 GB |
| SK-C1-10R-3_R1_001.fastq.gz | RNA-Seq | 11.8 GB |
| SK-C1-10R-3_R1_001.fastq.gz | RNA-Seq | 11.8 GB |
| SK-C1-10S-1_R1_001.fastq.gz | RNA-Seq | 10.8 GB |
| SK-C1-10S-1_R1_001.fastq.gz | RNA-Seq | 10.8 GB |
| SK-C1-10S-2_R1_001.fastq.gz | RNA-Seq | 11.7 GB |
| SK-C1-10S-2_R1_001.fastq.gz | RNA-Seq | 11.7 GB |
| SK-C1-10S-3_R1_001.fastq.gz | RNA-Seq | 11.2 GB |
| SK-C1-10S-3_R1_001.fastq.gz | RNA-Seq | 11.2 GB |
| SK-C1-D1_R1_001.fastq.gz | RNA-Seq | 10.7 GB |
| SK-C1-D1_R1_001.fastq.gz | RNA-Seq | 10.7 GB |
| SK-C1-D2_R1_001.fastq.gz | RNA-Seq | 10.8 GB |
| SK-C1-D2_R1_001.fastq.gz | RNA-Seq | 10.8 GB |
| SK-C1-D3_R1_001.fastq.gz | RNA-Seq | 10.4 GB |
| SK-C1-D3_R1_001.fastq.gz | RNA-Seq | 10.4 GB |
| SK-KO5-10R-1_R1_001.fastq.gz | RNA-Seq | 13.5 GB |
| SK-KO5-10R-1_R1_001.fastq.gz | RNA-Seq | 13.5 GB |
| SK-KO5-10R-2_R1_001.fastq.gz | RNA-Seq | 12.2 GB |
| SK-KO5-10R-2_R1_001.fastq.gz | RNA-Seq | 12.2 GB |
| SK-KO5-10R-3_R1_001.fastq.gz | RNA-Seq | 11.4 GB |
| SK-KO5-10R-3_R1_001.fastq.gz | RNA-Seq | 11.4 GB |
| SK-KO5-10S-1_R1_001.fastq.gz | RNA-Seq | 11.6 GB |
| SK-KO5-10S-1_R1_001.fastq.gz | RNA-Seq | 11.6 GB |
| SK-KO5-10S-2_R1_001.fastq.gz | RNA-Seq | 12.5 GB |
| SK-KO5-10S-2_R1_001.fastq.gz | RNA-Seq | 12.5 GB |
| SK-KO5-10S-3_R1_001.fastq.gz | RNA-Seq | 11.8 GB |
| SK-KO5-10S-3_R1_001.fastq.gz | RNA-Seq | 11.8 GB |
| SK-KO5-D1_R1_001.fastq.gz | RNA-Seq | 10.8 GB |
| SK-KO5-D1_R1_001.fastq.gz | RNA-Seq | 10.8 GB |
| SK-KO5-D2_R1_001.fastq.gz | RNA-Seq | 11.1 GB |
| SK-KO5-D2_R1_001.fastq.gz | RNA-Seq | 11.1 GB |
| SK-KO5-D3_R1_001.fastq.gz | RNA-Seq | 9.8 GB |
| SK-KO5-D3_R1_001.fastq.gz | RNA-Seq | 9.8 GB |
| SRR18300972.lite | RNA-Seq | 3.5 GB |
| SRR18300997.lite | RNA-Seq | 11.5 GB |
Potentially Related Datasets (4)
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
Remodeling of oncogenic transcriptomes by small-molecules targeting the RNA-binding protein NONO
Analysis Pipelines (4)
GSE198212 eCLIP Data Processing
7 steps
GSE222216 Data Processing
4 steps
geo_data_processing
GSE222216