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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• O-GlcNAc transferase (OGT) is crucial for cellular functions and collaborates with transcription regulators like cyclin-dependent kinase 12 (CDK12).
• CDK12 is a key transcription elongation kinase, and its activity is implicated in various cancers, including prostate cancer.

Purpose of the Study:

• To investigate the therapeutic potential of co-targeting OGT and CDK12 in prostate cancer.
• To identify novel therapeutic vulnerabilities associated with CDK12 inactivation in prostate cancer.

Main Methods:

• Utilized inhibitor- and knockdown-based strategies to assess the effects of OGT and CDK12 co-targeting.
• Employed glycoproteomics to analyze O-GlcNAcylation changes in response to CDK12 inhibition.
• Integrated glycoproteomics, gene essentiality, and clinical data from prostate cancer patients.

Main Results:

• Co-targeting OGT and CDK12 demonstrated toxicity towards prostate cancer cells.
• Short-term CDK12 inhibition led to hyper-O-GlcNAcylation of the spliceosome machinery.
• Identified serine-arginine protein kinase 1 (SRPK1) as a synthetic lethal partner with CDK12 inactivation.

Conclusions:

• Prostate cancer cells with reduced CDK12 activity are highly sensitive to OGT and SRPK1 inhibitors.
• Inactivating CDK12 mutations, prevalent in aggressive prostate cancer, suggest potential benefit from spliceosome-targeting therapies.