RRC ID 68132
Author Fukasawa K, Kadota T, Horie T, Tokumura K, Terada R, Kitaguchi Y, Park G, Ochiai S, Iwahashi S, Okayama Y, Hiraiwa M, Yamada T, Iezaki T, Kaneda K, Yamamoto M, Kitao T, Shirahase H, Hazawa M, Wong RW, Todo T, Hirao A, Hinoi E.
Title CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway.
Journal Oncogene
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.
Volume 40(15)
Pages 2803-2815
Published 2021-4-1
DOI 10.1038/s41388-021-01745-1
PII 10.1038/s41388-021-01745-1
PMID 33727660
MeSH Animals Brain Neoplasms / genetics Brain Neoplasms / metabolism* Brain Neoplasms / pathology Cyclin-Dependent Kinase 8 / genetics Cyclin-Dependent Kinase 8 / metabolism* Glioblastoma / genetics Glioblastoma / metabolism* Glioblastoma / pathology Humans Mice Neoplastic Stem Cells / metabolism* Neoplastic Stem Cells / pathology Proto-Oncogene Proteins c-myc / genetics Proto-Oncogene Proteins c-myc / metabolism* Signal Transduction
IF 7.971
Resource
Human and Animal Cells 293T(RCB2202)