CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway
CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway
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DOI：
10.1038/s41388-021-01745-1
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发表时间：
2021-03-16
期刊：
影响因子：
8
通讯作者：
Hinoi, Eiichi
中科院分区：
文献类型：
--
作者：
Fukasawa, Kazuya;Kadota, Takuya;Hinoi, Eiichi
胶质母细胞瘤（GBM）是恶性程度最高的胶质瘤。胶质瘤干细胞（GSCs）由于其自我更新潜力和致瘤性，有助于GBM的发生、进展和复发。周期蛋白依赖性激酶8 （CDK8）属于与转录相关的CDK家族。尽管CDK8已被证明与几种类型的恶性肿瘤有关，但其在胶质瘤形成中的功能作用和机制仍不清楚。在这里，我们展示了CDK8如何在维持GSCs的干性和致瘤性中发挥重要作用。通过shRNA或CRISPR干扰对CDK8的基因抑制导致患者源性GSCs的自我更新潜能和致瘤性丧失，而干细胞转录因子c-MYC的异位表达可显著挽救这种能力。此外，我们证明CDK8的药理抑制显著减弱了GSCs的自我更新潜能和致瘤性。CDK8在人GBM组织中的表达明显高于正常脑组织，且其表达与人GBM标本中c-MYC、SOX2等干细胞标志物呈正相关。此外，CDK8表达与GBM患者的低生存率相关。总的来说，这些发现强调了CDK8-c-MYC轴在维持GSCs的干性和致瘤性中的重要性；这些发现还确定了CDK8-c-MYC轴是gsc定向治疗的潜在靶点。
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.