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CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway

Oncogene volume 40, pages 2803–2815 (2021)Cite this article

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Abstract

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.

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Fig. 1: CDK8 silencing suppresses growth and self-renewal of GSCs in vitro.
Fig. 2: CDK8 silencing disrupts the tumor growth of GSCs in vivo.
Fig. 3: CDK8 overexpression enhances growth and self-renewal of GSCs in vitro.
Fig. 4: Overexpression of c-MYC partially restores the suppressive effect of CDK8 silencing on GSC phenotypes.
Fig. 5: The novel CDK8 kinase inhibitor KY-065 has inhibitory effect on GSC phenotypes.
Fig. 6: CDK8 is highly expressed in GBM specimens, shows a positive correlation with stem cell markers, and is associated with poor prognosis in GBM patients.

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Acknowledgements

We wish to thank Dr. H. Hojo (University of Tokyo) for technical training in RNA-seq data analysis. RNA-seq data and survival analysis were performed using the super-computing resource provided by Human Genome Center, the Institute of Medical Science, the University of Tokyo. This work was supported in part by the Japan Society for the Promotion of Science (20H03407 to EH), and the Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University.

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  1. These authors equally contributed: Kazuya Fukasawa, Takuya Kadota, Tetsuhiro Horie

Authors and Affiliations

  1. Laboratory of Pharmacology, Department of Bioactive Molecules, Gifu Pharmaceutical University, Gifu, Japan

    Kazuya Fukasawa, Takuya Kadota, Tetsuhiro Horie, Kazuya Tokumura, Ryuichi Terada, Yuka Kitaguchi, Gyujin Park, Shinsuke Ochiai, Sayuki Iwahashi, Yasuka Okayama, Manami Hiraiwa, Takanori Yamada, Takashi Iezaki & Eiichi Hinoi

  2. Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd, Kyoto, Japan

    Takuya Kadota, Megumi Yamamoto, Tatsuya Kitao & Hiroaki Shirahase

  3. Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan

    Yuka Kitaguchi & Katsuyuki Kaneda

  4. Cell-Bionomics Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan

    Masaharu Hazawa & Richard W. Wong

  5. WPI Nano Life Science Institute (WPI‐Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan

    Richard W. Wong & Atsushi Hirao

  6. Division of Innovative Cancer Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Tomoki Todo

  7. Cancer and Stem Cell Research Program, Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan

    Atsushi Hirao

  8. United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan

    Eiichi Hinoi

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  1. Kazuya Fukasawa
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Correspondence to Eiichi Hinoi.

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TKadota, MY, TKitao, and HS are employees of Kyoto Pharmaceutical Industries, Ltd. EH is supported by a research fund from Kyoto Pharmaceutical Industries, Ltd. The other authors declare no potential competing interests.

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Fukasawa, K., Kadota, T., Horie, T. et al. CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway. Oncogene 40, 2803–2815 (2021). https://doi.org/10.1038/s41388-021-01745-1

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