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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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References

  1. Ostrom QT, Gittleman H, Kruchko C, Barnholtz-Sloan JS. Primary brain and other central nervous system tumors in Appalachia: regional differences in incidence, mortality, and survival. J Neurooncol. 2019;142:27–38.

    Article  CAS  PubMed  Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

    Article  CAS  PubMed  Google Scholar 

  3. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.

    Article  CAS  PubMed  Google Scholar 

  4. Bhat KPL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, et al. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24:331–46.

    Article  CAS  PubMed  Google Scholar 

  5. Venere M, Fine HA, Dirks PB, Rich JN. Cancer stem cells in gliomas: identifying and understanding the apex cell in cancer’s hierarchy. Glia. 2011;59:1148–54.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Waghmare I, Roebke A, Minata M, Kango-Singh M, Nakano I. Intercellular cooperation and competition in brain cancers: lessons from Drosophila and human studies. Stem Cells Transl Med. 2014;3:1262–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Meyer M, Reimand J, Lan X, Head R, Zhu X, Kushida M, et al. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc Natl Acad Sci USA. 2015;112:851–6.

    Article  CAS  PubMed  Google Scholar 

  8. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153:139–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev. 2015;29:1203–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhou W, Ke SQ, Huang Z, Flavahan W, Fang X, Paul J, et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol. 2015;17:170–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lim S, Kaldis PCdks. cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013;140:3079–93.

    Article  CAS  PubMed  Google Scholar 

  13. Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014;15:122.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.

    Article  CAS  PubMed  Google Scholar 

  15. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2018;379:2582

    Article  Google Scholar 

  16. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36.

    Article  CAS  PubMed  Google Scholar 

  17. Laderian B, Fojo T. CDK4/6 Inhibition as a therapeutic strategy in breast cancer: palbociclib, ribociclib, and abemaciclib. Semin Oncol. 2017;44:395–403.

    Article  CAS  PubMed  Google Scholar 

  18. Sledge GW Jr., Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875–84.

    Article  CAS  PubMed  Google Scholar 

  19. Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125:443–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Conaway RC, Conaway JW. Function and regulation of the mediator complex. Curr Opin Genet Dev. 2011;21:225–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Taatjes DJ. The human Mediator complex: a versatile, genome-wide regulator of transcription. Trends Biochem Sci. 2010;35:315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Galbraith MD, Allen MA, Bensard CL, Wang X, Schwinn MK, Qin B, et al. HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia. Cell. 2013;153:1327–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Knuesel MT, Meyer KD, Donner AJ, Espinosa JM, Taatjes DJ. The human CDK8 subcomplex is a histone kinase that requires Med12 for activity and can function independently of mediator. Mol Cell Biol. 2009;29:650–61.

    Article  CAS  PubMed  Google Scholar 

  24. Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, et al. CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature. 2008;455:547–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xu D, Li CF, Zhang X, Gong Z, Chan CH, Lee SW, et al. Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis. Nat Commun. 2015;6:6641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brägelmann J, Klümper N, Offermann A, von Mässenhausen A, Böhm D, Deng M, et al. Pan-cancer analysis of the mediator complex transcriptome identifies CDK19 and CDK8 as therapeutic targets in advanced prostate cancer. Clin Cancer Res. 2017;23:1829–40.

    Article  PubMed  Google Scholar 

  27. Xu W, Wang Z, Zhang W, Qian K, Li H, Kong D, et al. Mutated K-ras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/β-catenin signaling pathway. Cancer Lett. 2015;356:613–27.

    Article  CAS  PubMed  Google Scholar 

  28. Kapoor A, Goldberg MS, Cumberland LK, Ratnakumar K, Segura MF, Emanuel PO, et al. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature. 2010;468:1105–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature. 2015;526:273–6.

  30. Gu W, Wang C, Li W, Hsu FN, Tian L, Zhou J, et al. Tumor-suppressive effects of CDK8 in endometrial cancer cells. Cell Cycle. 2013;12:987–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Adler AS, McCleland ML, Truong T, Lau S, Modrusan Z, Soukup TM, et al. CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. Cancer Res. 2012;72:2129–39.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang JF, Zhang JS, Zhao ZH, Yang PB, Ji SF, Li N, et al. MicroRNA-770 affects proliferation and cell cycle transition by directly targeting CDK8 in glioma. Cancer Cell Int. 2018;18:195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, et al. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity. 2013;38:250–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang J, Wang H, Li Z, Wu Q, Lathia JD, McLendon RE, et al. c-Myc is required for maintenance of glioma cancer stem cells. PLoS ONE. 2008;3:e3769.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, et al. Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harb Symp Quant Biol. 2008;73:427–37.

    Article  CAS  PubMed  Google Scholar 

  36. Broude EV, Győrffy B, Chumanevich AA, Chen M, McDermott MS, Shtutman M, et al. Expression of CDK8 and CDK8-interacting genes as potential biomarkers in breast cancer. Curr Cancer Drug Targets. 2015;15:739–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kitao T, Ito Y, Fukui M, Yamamoto M, Shoji Y, Takeda S, et al. A novel oral anti-osteoporosis drug with osteogenesis-promoting effects via osteoblast differentiation. Yakugaku Zasshi. 2019;139:19–25.

  38. Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol. 2009;11:1275–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wasylishen AR, Penn LZ. Myc: the beauty and the beast. Genes Cancer. 2010;1:532–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009;15:6479–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  CAS  PubMed  Google Scholar 

  42. Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, et al. Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. Embo J. 2000;19:263–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, et al. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011;20:427–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Quevedo M, Meert L, Dekker MR, Dekkers DHW, Brandsma JH, van den Berg DLC, et al. Mediator complex interaction partners organize the transcriptional network that defines neural stem cells. Nat Commun. 2019;10:2669.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Alarcón C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell. 2009;139:757–69.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Serrao A, Jenkins LM, Chumanevich AA, Horst B, Liang J, Gatza ML, et al. Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer. Oncogene. 2018;37:4792–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Martinez-Fabregas J, Wang L, Pohler E, Cozzani A, Wilmes S, Kazemian M, et al. CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci. Cell Rep. 2020;33:108545.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Chen M, Liang J, Ji H, Yang Z, Altilia S, Hu B, et al. CDK8/19 Mediator kinases potentiate induction of transcription by NFκB. Proc Natl Acad Sci USA. 2017;114:10208–13.

    Article  CAS  PubMed  Google Scholar 

  49. Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K, Miyazono K. Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell. 2009;5:504–14.

    Article  CAS  PubMed  Google Scholar 

  50. Rinkenbaugh AL, Cogswell PC, Calamini B, Dunn DE, Persson AI, Weiss WA, et al. IKK/NF-κB signaling contributes to glioblastoma stem cell maintenance. Oncotarget. 2016;7:69173–87.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sachdeva R, Wu M, Johnson K, Kim H, Celebre A, Shahzad U, et al. BMP signaling mediates glioma stem cell quiescence and confers treatment resistance in glioblastoma. Sci Rep. 2019;9:14569.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Shi Y, Guryanova OA, Zhou W, Liu C, Huang Z, Fang X. et al. Ibrutinib inactivates BMX-STAT3 in glioma stem cells to impair malignant growth and radioresistance. Sci Transl Med. 2018;10.

  53. Putz EM, Gotthardt D, Hoermann G, Csiszar A, Wirth S, Berger A, et al. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumorsurveillance. Cell Rep. 2013;4:437–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Witalisz-Siepracka A, Gotthardt D, Prchal-Murphy M, Didara Z, Menzl I, Prinz D, et al. NK Cell-Specific CDK8 Deletion Enhances Antitumor Responses. Cancer Immunol Res. 2018;6:458–66.

    Article  CAS  PubMed  Google Scholar 

  55. McCleland ML, Soukup TM, Liu SD, Esensten JH, de Sousa e Melo F, Yaylaoglu M, et al. Cdk8 deletion in the Apc(Min) murine tumour model represses EZH2 activity and accelerates tumourigenesis. J Pathol. 2015;237:508–19.

    Article  CAS  PubMed  Google Scholar 

  56. Westerling T, Kuuluvainen E, Mäkelä TP. Cdk8 is essential for preimplantation mouse development. Mol Cell Biol. 2007;27:6177–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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