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| Status |
Public on Aug 18, 2020 |
| Title |
Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
O-GlcNAc transferase (OGT) is a nutrient-sensitive glycosyltransferase that is overexpressed in prostate cancer, the most common cancer in males. We recently developed specific and potent inhibitor targeting this enzyme, and here we report a synthetic lethality screen using this compound. Our screen identified pan-cyclin-dependent kinase (CDK) inhibitor AT7519 as lethal in combination with OGT inhibition. Follow-up chemical and genetic approaches identified CDK9 as the major target for synthetic lethality with OGT inhibition in prostate cancer cells. OGT expression is regulated through retention of the fourth intron in the gene and CDK9 inhibition blunted this regulatory mechanism. CDK9 phosphorylates carboxy-terminal domain (CTD) of RNA Polymerase II (RNA Pol II) to promote transcription elongation. We showed that OGT inhibition augments effects of CDK9 inhibitors on CTD phosphorylation and general transcription. Finally, the combined inhibition of both OGT and CDK9 blocked growth of organoids derived from metastatic prostate cancer patients but had minimal effects on normal prostate spheroids. We report a novel synthetic lethal interaction between inhibitors of OGT and CDK9 that specifically kills prostate cancer cells but not normal cells. Our study highlights the potential of combining OGT inhibitors with other treatments to exploit cancer specific vulnerabilities.
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| Overall design |
mRNA profiles of LNCaP cells treated with control, OGT inhibitor (40μM OSMI-2), CDK inhibitor (0.5μM AT7519) and Combination treatment (0.5μM AT7519 + 40μM OSMI-2), for 4 hours prior to harvesting.
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| Contributor(s) |
Itkonen HM, Poulose N, Steele RE, Martin SE, Levine ZG, Duveau DY, Carelli R, Singh R, Urbanucci A, Loda M, Thomas C, Mills IG, Walker S |
| Citation(s) |
32611550 |
| Submission date |
Jul 09, 2018 |
| Last update date |
Aug 19, 2020 |
| Contact name |
Rebecca Elizabeth Steele |
| E-mail(s) |
rebecca.steele@icr.ac.uk
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| Organization name |
Queen's University Belfast
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| Department |
CCRCB
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| Street address |
97 Lisburn Road
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| City |
Belfast |
| ZIP/Postal code |
BT97AE |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA480226 |
| SRA |
SRP152818 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE116778_Drug_normalised_counts.txt.gz |
1.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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