Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast BT9 7AE, United Kingdom.
Glycobiology. 2022 Aug 18;32(9):751-759. doi: 10.1093/glycob/cwac038.
Co-targeting of O-GlcNAc transferase (OGT) and the transcriptional kinase cyclin-dependent kinase 9 (CDK9) is toxic to prostate cancer cells. As OGT is an essential glycosyltransferase, identifying an alternative target showing similar effects is of great interest. Here, we used a multiomics approach (transcriptomics, metabolomics, and proteomics) to better understand the mechanistic basis of the combinatorial lethality between OGT and CDK9 inhibition. CDK9 inhibition preferentially affected transcription. In contrast, depletion of OGT activity predominantly remodeled the metabolome. Using an unbiased systems biology approach (weighted gene correlation network analysis), we discovered that CDK9 inhibition alters mitochondrial activity/flux, and high OGT activity is essential to maintain mitochondrial respiration when CDK9 activity is depleted. Our metabolite profiling data revealed that pantothenic acid (vitamin B5) is the metabolite that is most robustly induced by both OGT and OGT+CDK9 inhibitor treatments but not by CDK9 inhibition alone. Finally, supplementing prostate cancer cell lines with vitamin B5 in the presence of CDK9 inhibitor mimics the effects of co-targeting OGT and CDK9.
靶向 O-连接 N-乙酰氨基葡萄糖转移酶（OGT）和转录激酶细胞周期蛋白依赖性激酶 9（CDK9）的联合抑制对前列腺癌细胞具有细胞毒性。由于 OGT 是一种必需的糖基转移酶，因此寻找具有相似作用的替代靶标非常重要。在这里，我们使用多组学方法（转录组学、代谢组学和蛋白质组学）来更好地理解 OGT 和 CDK9 抑制联合致死的机制基础。CDK9 抑制优先影响转录。相比之下，OGT 活性的耗竭主要重塑了代谢组。使用无偏的系统生物学方法（加权基因相关网络分析），我们发现 CDK9 抑制改变了线粒体的活性/通量，并且当 CDK9 活性被耗尽时，高 OGT 活性对于维持线粒体呼吸是必需的。我们的代谢物分析数据表明，泛酸（维生素 B5）是最受 OGT 和 OGT+CDK9 抑制剂处理诱导的代谢物，但不受 CDK9 抑制剂单独作用的影响。最后，在 CDK9 抑制剂存在的情况下，用维生素 B5 补充前列腺癌细胞系可以模拟联合靶向 OGT 和 CDK9 的效果。
