Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, PL 63 (Haartmaninkatu 8), 00014, Helsinki, Finland.
Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway.
J Cancer Res Clin Oncol. 2023 Jul;149(8):5255-5263. doi: 10.1007/s00432-022-04475-3. Epub 2022 Nov 18.
Prostate cancer (PC) is successfully treated with anti-androgens; however, a significant proportion of patients develop resistance against this therapy. Anti-androgen-resistant disease (castration-resistant prostate cancer; CRPC) is currently incurable. Cyclin-dependent kinase 7 (CDK7) is positioned to positively regulate both cell cycle and transcription, the two features critical for the rapid proliferation of the CRPC cells. Here, we assess if CDK7 is a viable target to halt the proliferation of CRPC cells.
We use recently developed clinically relevant compounds targeting CDK7 and multiple cell proliferation assays to probe the importance of this kinase for the proliferation of normal, androgen-dependent, and CRPC cells. PC patient data were used to evaluate expression of CDK7 at different disease-stages. Finally, comprehensive glycoproteome-profiling was performed to evaluate CDK7 inhibitor effects on androgen-dependent and CRPC cells.
We show that CDK7 is overexpressed in PC patients with poor prognosis, and that CRPC cells are highly sensitive to compounds targeting CDK7. Inhibition of O-GlcNAc transferase sensitizes the CRPC, but not androgen-dependent PC cells, to CDK7 inhibitors. Glycoproteome-profiling revealed that CDK7 inhibition induces hyper-O-GlcNAcylation of the positive transcription elongation complex (pTEFB: CDK9 and CCNT1) in the CRPC cells. Accordingly, co-targeting of CDK7 and CDK9 synergistically blocks the proliferation of the CRPC cells but does not have anti-proliferative effects in the normal prostate cells.
We show that CRPC cells, but not normal prostate cells, are addicted on the high activity of the key transcriptional kinases, CDK7 and CDK9.
前列腺癌 (PC) 通过抗雄激素治疗可获得成功，但相当一部分患者会对该治疗产生耐药。目前，抗雄激素耐药疾病（去势抵抗性前列腺癌；CRPC）无法治愈。细胞周期蛋白依赖性激酶 7 (CDK7) 位于正调控细胞周期和转录的位置，这两个特征对 CRPC 细胞的快速增殖至关重要。在这里，我们评估 CDK7 是否是阻止 CRPC 细胞增殖的可行靶点。
我们使用最近开发的针对 CDK7 的临床相关化合物和多种细胞增殖测定法，探究该激酶对正常、雄激素依赖性和 CRPC 细胞增殖的重要性。使用 PC 患者的数据来评估 CDK7 在不同疾病阶段的表达。最后，进行全面的糖蛋白组谱分析，以评估 CDK7 抑制剂对雄激素依赖性和 CRPC 细胞的影响。
我们表明，CDK7 在预后不良的 PC 患者中过表达，CRPC 细胞对靶向 CDK7 的化合物高度敏感。抑制 O-连接的 N-乙酰葡萄糖胺转移酶使 CRPC 细胞而不是雄激素依赖性 PC 细胞对 CDK7 抑制剂敏感。糖蛋白组谱分析显示，CDK7 抑制导致 CRPC 细胞中正向转录延伸复合物（pTEFB：CDK9 和 CCNT1）的 O-连接的 N-乙酰葡萄糖胺过度修饰。相应地，CDK7 和 CDK9 的联合靶向协同阻断 CRPC 细胞的增殖，但在正常前列腺细胞中没有抗增殖作用。
我们表明，CRPC 细胞而非正常前列腺细胞依赖于关键转录激酶 CDK7 和 CDK9 的高活性。
