Laboratory of Pharmacology, Department of Bioactive Molecules, Gifu Pharmaceutical University, Gifu, Japan.
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd, Kyoto, Japan.
Oncogene. 2021 Apr;40(15):2803-2815. doi: 10.1038/s41388-021-01745-1. Epub 2021 Mar 16.
Glioblastoma (GBM) is the most malignant form of glioma. Glioma stem cells (GSCs) contribute to the initiation, progression, and recurrence of GBM as a result of their self-renewal potential and tumorigenicity. Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related CDK family. Although CDK8 has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in gliomagenesis remain largely unknown. Here, we demonstrate how CDK8 plays an essential role in maintaining stemness and tumorigenicity in GSCs. The genetic inhibition of CDK8 by shRNA or CRISPR interference resulted in an abrogation of the self-renewal potential and tumorigenicity of patient-derived GSCs, which could be significantly rescued by the ectopic expression of c-MYC, a stem cell transcription factor. Moreover, we demonstrated that the pharmacological inhibition of CDK8 significantly attenuated the self-renewal potential and tumorigenicity of GSCs. CDK8 expression was significantly higher in human GBM tissues than in normal brain tissues, and its expression was positively correlated with stem cell markers including c-MYC and SOX2 in human GBM specimens. Additionally, CDK8 expression is associated with poor survival in GBM patients. Collectively, these findings highlight the importance of the CDK8-c-MYC axis in maintaining stemness and tumorigenicity in GSCs; these findings also identify the CDK8-c-MYC axis as a potential target for GSC-directed therapy.
胶质母细胞瘤（GBM）是最恶性的神经胶质瘤形式。神经胶质瘤干细胞（GSCs）由于其自我更新能力和致瘤性，促进 GBM 的发生、发展和复发。细胞周期蛋白依赖性激酶 8（CDK8）属于转录相关 CDK 家族。虽然 CDK8 已被证明与多种类型癌症的恶性有关，但它在神经胶质瘤发生中的功能作用和机制在很大程度上仍不清楚。在这里，我们证明了 CDK8 如何在维持 GSCs 的干性和致瘤性方面发挥重要作用。通过 shRNA 或 CRISPR 干扰对 CDK8 的基因抑制导致患者来源的 GSCs 的自我更新能力和致瘤性丧失，而干细胞转录因子 c-MYC 的异位表达可显著挽救这种丧失。此外，我们证明了 CDK8 的药理学抑制可显著减弱 GSCs 的自我更新能力和致瘤性。CDK8 在人 GBM 组织中的表达明显高于正常脑组织，其表达与人 GBM 标本中的干细胞标志物包括 c-MYC 和 SOX2 呈正相关。此外，CDK8 的表达与 GBM 患者的不良生存相关。总之，这些发现强调了 CDK8-c-MYC 轴在维持 GSCs 的干性和致瘤性方面的重要性；这些发现还确定了 CDK8-c-MYC 轴作为针对 GSC 的治疗的潜在靶点。
