Inhibition of O-GlcNAc Transferase Renders Prostate Cancer Cells Dependent on CDK9
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 01, 2020
- Source ID
- 10.1158/1541-7786.mcr-20-0339
Entities
People
- Alfonso Urbanucci
- Craig J. Thomas
- Damien Y Duveau
- Harri Itkonen
- Ian G Mills
- Massimo Loda
- Ninu Poulose
- Rebecca E. Steele
- Reema Singh
- Ryan Carelli
- Sara E S Martin
- Suzanne Walker
- Zebulon G. Levine
Organizations
- Harvard Medical School
- National Cancer Institute
- National Institutes of Health
- New York Genome Center
- Norwegian Cancer Society
- Oslo University Hospital
- Prostate Cancer UK
- Queen's University Belfast
- Research Council of Norway
- University of Oslo
- University of Oxford
- Weill Cornell Medicine