2. Academic Validation
  3. Compromised CDK12 activity causes dependency on the high activity of O-GlcNAc transferase

Compromised CDK12 activity causes dependency on the high activity of O-GlcNAc transferase

  • Glycobiology. 2024 Oct 3:cwae081. doi: 10.1093/glycob/cwae081.
Satu Pallasaho 1,  Aishwarya Gondane 1,  Julia Kutz 2,  Jing Liang 1,  Shivani Yalala 1,  Damien Y Duveau 3,  Helmut Pospiech 2 4,  Craig J Thomas 3 5,  Massimo Loda 6 7 8,  Harri M Itkonen 1 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
  • 2 Project group Biochemistry, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena D-07745, Germany.
  • 3 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, United States.
  • 4 University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Life Science Center, Düsseldorf D-40225, Germany.
  • 5 Lymphoid Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, United States.
  • 6 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York 10021, United States.
  • 7 The Broad Institute of Harvard and MIT, Cambridge, MA 02142, United States.
  • 8 The New York Genome Center, New York, New York 10013, United States.
PMID: 39361894 DOI: 10.1093/glycob/cwae081
Abstract

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.

Keywords

O-GlcNAc transferase; cyclin-dependent kinase 12; prostate cancer; spliceosome; synthetic lethality.

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