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Series GSE116778 Query DataSets for GSE116778
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
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.
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.
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
Organization name Queen's University Belfast
Department CCRCB
Street address 97 Lisburn Road
City Belfast
ZIP/Postal code BT97AE
Country United Kingdom
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (8)
GSM3261821 LnCaP_Control_Replicate1
GSM3261822 LnCaP_Control_Replicate2
GSM3261823 LnCaP_OSMI2_Replicate1
BioProject PRJNA480226
SRA SRP152818

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Supplementary file Size Download File type/resource
GSE116778_Drug_normalised_counts.txt.gz 1.1 Mb (ftp)(http) TXT
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