2. Academic Validation
  3. Inhibition of O-GlcNAc Transferase Renders Prostate Cancer Cells Dependent on CDK9

Inhibition of O-GlcNAc Transferase Renders Prostate Cancer Cells Dependent on CDK9

  • Mol Cancer Res. 2020 Oct;18(10):1512-1521. doi: 10.1158/1541-7786.MCR-20-0339.
Harri M Itkonen 1 2 3,  Ninu Poulose 4 5,  Rebecca E Steele 4,  Sara E S Martin 2,  Zebulon G Levine 2,  Damien Y Duveau 6,  Ryan Carelli 3,  Reema Singh 4 5,  Alfonso Urbanucci 7 8 9,  Massimo Loda 3 10 11,  Craig J Thomas 6 12,  Ian G Mills 1 4 5,  Suzanne Walker 13
Affiliations

Affiliations

  • 1 Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, Oslo, Norway. h.m.itkonen@gmail.com ian.mills@linacre.ox.ac.uk suzanne_walker@hms.harvard.edu.
  • 2 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.
  • 3 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York.
  • 4 PCUK/Movember Centre of Excellence for Prostate Cancer Research, Patrick G Johnston Centre for Cancer Research (PGJCCR), Queen's University Belfast, Belfast, United Kingdom.
  • 5 Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
  • 6 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
  • 7 Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, Oslo, Norway.
  • 8 Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
  • 9 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
  • 10 The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • 11 The New York Genome Center, New York, New York.
  • 12 Lymphoid Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • 13 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts. h.m.itkonen@gmail.com ian.mills@linacre.ox.ac.uk suzanne_walker@hms.harvard.edu.
PMID: 32611550 DOI: 10.1158/1541-7786.MCR-20-0339
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. IMPLICATIONS: The primary contribution of OGT to cell proliferation is unknown, and in this study, we used a compound screen to indicate that OGT and CDK9 collaborate to sustain a Cancer cell-specific pro-proliferative program. A better understanding of how OGT and CDK9 cross-talk will refine our understanding of this novel synthetic lethal interaction.

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