Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9
O-GlcNAc transferase (OGT) is a nutrient-sensitive glycosyltransferase that is overexpressed in prostate cancer, the most common cancer in males. We recently developed a specific and potent inhibitor targeting this enzyme, and here, we report a synthetic lethality screen using this compound. Our scr...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Association for Cancer Research
2020
|
| _version_ | 1797072107656445952 |
|---|---|
| author | Itkonen, HM Poulose, N Steele, RE Martin, SES Levine, ZG Duveau, DY Carelli, R Singh, R Urbanucci, A Loda, M Thomas, CJ Mills, IG Walker, S |
| author_facet | Itkonen, HM Poulose, N Steele, RE Martin, SES Levine, ZG Duveau, DY Carelli, R Singh, R Urbanucci, A Loda, M Thomas, CJ Mills, IG Walker, S |
| author_sort | Itkonen, HM |
| collection | OXFORD |
| description | O-GlcNAc transferase (OGT) is a nutrient-sensitive glycosyltransferase that is overexpressed in prostate cancer, the most common cancer in males. We recently developed a 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 to promote transcription elongation. We show 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 patients with metastatic prostate cancer, 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. |
| first_indexed | 2024-03-06T23:02:53Z |
| format | Journal article |
| id | oxford-uuid:62c92533-1ca9-4ec1-af08-f82a3025bee0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:02:53Z |
| publishDate | 2020 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | oxford-uuid:62c92533-1ca9-4ec1-af08-f82a3025bee02022-03-26T18:08:30ZInhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:62c92533-1ca9-4ec1-af08-f82a3025bee0EnglishSymplectic ElementsAmerican Association for Cancer Research2020Itkonen, HMPoulose, NSteele, REMartin, SESLevine, ZGDuveau, DYCarelli, RSingh, RUrbanucci, ALoda, MThomas, CJMills, IGWalker, SO-GlcNAc transferase (OGT) is a nutrient-sensitive glycosyltransferase that is overexpressed in prostate cancer, the most common cancer in males. We recently developed a 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 to promote transcription elongation. We show 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 patients with metastatic prostate cancer, 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. |
| spellingShingle | Itkonen, HM Poulose, N Steele, RE Martin, SES Levine, ZG Duveau, DY Carelli, R Singh, R Urbanucci, A Loda, M Thomas, CJ Mills, IG Walker, S Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9 |
| title | Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9 |
| title_full | Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9 |
| title_fullStr | Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9 |
| title_full_unstemmed | Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9 |
| title_short | Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9 |
| title_sort | inhibition of o glcnac transferase renders prostate cancer cells dependent on cdk9 |
| work_keys_str_mv | AT itkonenhm inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT poulosen inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT steelere inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT martinses inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT levinezg inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT duveaudy inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT carellir inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT singhr inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT urbanuccia inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT lodam inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT thomascj inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT millsig inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 AT walkers inhibitionofoglcnactransferaserendersprostatecancercellsdependentoncdk9 |