Pallasaho Satu, Gondane Aishwarya, Kutz Julia, Liang Jing, Yalala Shivani, Duveau Damien Y, Pospiech Helmut, Thomas Craig J, Loda Massimo, Itkonen Harri M
Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
Project group Biochemistry, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena D-07745, Germany.
Glycobiology. 2024 Dec 10;34(12). doi: 10.1093/glycob/cwae081.
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.
O-连接的N-乙酰葡糖胺转移酶（OGT）与转录调节因子相互协作，其中包括细胞周期蛋白依赖性激酶12（CDK12），即主要的转录延伸激酶。在此，我们采用基于抑制剂和基因敲低的策略来表明，共同靶向OGT和CDK12对前列腺癌细胞具有毒性。OGT催化所有核质O-连接的N-乙酰葡糖胺化修饰，并且由于其在高等真核生物中的不可或缺性，它并非理想的药物靶点。我们的糖蛋白质组学数据显示，在不同的前列腺癌模型中，短期抑制CDK12会诱导剪接体机制的O-连接的N-乙酰葡糖胺化修饰过度。通过整合来自CDK12突变型前列腺癌患者的糖蛋白质组学、基因必需性和临床数据，我们确定非必需的丝氨酸-精氨酸蛋白激酶1（SRPK1）是与CDK12失活具有合成致死性的伙伴。如果正常细胞和癌细胞的CDK12活性降低，它们对OGT和SRPK1的抑制剂都会变得高度敏感。CDK12的失活突变在侵袭性前列腺癌中富集，我们提出这些患者将从靶向剪接体的治疗中受益。
