CDK12 活性下降会导致对高活性 O-GlcNAc 转移酶的依赖。

IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Satu Pallasaho, Aishwarya Gondane, Julia Kutz, Jing Liang, Shivani Yalala, Damien Y Duveau, Helmut Pospiech, Craig J Thomas, Massimo Loda, Harri M Itkonen
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引用次数: 0

摘要

O-GlcNAc转移酶(OGT)与转录调节因子(包括主要的转录延伸激酶--细胞周期蛋白依赖性激酶12(CDK12))相互协调。在这里,我们使用抑制剂和基因敲除策略证明,OGT 和 CDK12 的共同靶向对前列腺癌细胞具有毒性。OGT催化所有核细胞质的O-GlcNA酰化,由于其在高等真核生物中的重要性,它并不是理想的药物靶点。我们的糖蛋白组学数据显示,在不同的前列腺癌模型中,短期的 CDK12 抑制会诱导剪接体机械的 O-GlcNAcylation 过度。通过整合 CDK12 突变前列腺癌患者的糖蛋白组学、基因本质和临床数据,我们发现非本质丝氨酸-精氨酸蛋白激酶 1 (SRPK1) 是 CDK12 失活的合成致死伙伴。如果 CDK12 的活性降低,正常细胞和癌细胞都会对 OGT 和 SRPK1 的抑制剂高度敏感。CDK12 的失活突变在侵袭性前列腺癌中很常见,我们认为这些患者将受益于针对剪接体的治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Glycobiology
Glycobiology 生物-生化与分子生物学
CiteScore
7.50
自引率
4.70%
发文量
73
审稿时长
3 months
期刊介绍: Established as the leading journal in the field, Glycobiology provides a unique forum dedicated to research into the biological functions of glycans, including glycoproteins, glycolipids, proteoglycans and free oligosaccharides, and on proteins that specifically interact with glycans (including lectins, glycosyltransferases, and glycosidases). Glycobiology is essential reading for researchers in biomedicine, basic science, and the biotechnology industries. By providing a single forum, the journal aims to improve communication between glycobiologists working in different disciplines and to increase the overall visibility of the field.
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