Compromised CDK12 activity causes dependency on the high activity of O-GlcNAc transferase
O-GlcNAc transferase (OGT) coordinates with regulators of transcription, including cyclin-dependent kinase 12 (CDK12), the major transcription elongation kinase. Here, we use inhibitor- and knockdown-based strategies to show that co-targeting of OGT and CDK12 is toxic to prostate cancer cells. OGT catalyzes all nucleocytoplasmic O-GlcNAcylation and due to its essentiality in higher eukaryotes, it is not an ideal drug target. Our glycoproteomics-data revealed that short-term CDK12 inhibition induces hyper-O-GlcNAcylation of the spliceosome-machinery in different models of prostate cancer. By integrating our glycoproteomics-, gene essentiality- and clinical-data from CDK12 mutant prostate cancer patients, we identify the non-essential serine-arginine protein kinase 1 (SRPK1) as a synthetic lethal partner with CDK12-inactivation. Both normal and cancer cells become highly sensitive against inhibitors of OGT and SRPK1 if they have lowered activity of CDK12. Inactivating mutations in CDK12 are enriched in aggressive prostate cancer, and we propose that these patients would benefit from therapy targeting the spliceosome.
Authors
- Helmut Pospiech (ORCID: https://orcid.org/0000-0002-5255-0747)
- Damien Duveau (ORCID: https://orcid.org/0000-0001-9954-7126)
- Craig J. Thomas (ORCID: https://orcid.org/0000-0001-9386-9001)
- Satu Pallasaho (ORCID: https://orcid.org/0000-0002-0214-8725)
- Harri M. Itkonen (ORCID: https://orcid.org/0000-0002-5194-7064)
- Julia Kutz
- Massimo Loda (ORCID: https://orcid.org/0000-0001-9674-8379)
- Aishwarya Gondane (ORCID: https://orcid.org/0000-0002-7495-2472)
- Shivani Yalala (ORCID: https://orcid.org/0009-0007-6105-8563)
- Jing Liang (ORCID: https://orcid.org/0009-0003-2513-6764)
Institutions
- Broad Institute (US)
- University of Helsinki (FI)
- NewYork–Presbyterian Hospital (US)
- Cornell University (US)
- New York Hospital Queens (US)
- Düsseldorf University Hospital (DE)
- Presbyterian Hospital (US)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Life Science Center Düsseldorf (Germany) (DE)
- National Center for Advancing Translational Sciences (US)
- Center for Cancer Research (US)
- New York Genome Center (US)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Glycobiology
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1093/glycob/cwae081
- Citations
- 4
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Helsingin Yliopisto
- Australian Government
- Gottfried Wilhelm Leibniz Universität Hannover
- Magnus Ehrnroothin Säätiö
- China Scholarship Council
- Emil Aaltosen Säätiö
- Syöpäsäätiö
- Otto A. Malm Lahjoitusrahasto
- Waldemar von Frenckells Stiftelse
- National Institutes of Health
- Leibniz-Gemeinschaft
- Jenny ja Antti Wihurin Rahasto