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

Fukasawa, Kazuya; Kadota, Takuya; Horie, Tetsuhiro; Tokumura, Kazuya; Terada, Ryuichi; Kitaguchi, Yuka; Park, Gyujin; Ochiai, Shinsuke; Iwahashi, Sayuki; Okayama, Yasuka; Hiraiwa, Manami; Yamada, Takanori; Iezaki, Takashi; Kaneda, Katsuyuki; Yamamoto, Megumi; Kitao, Toshio; Shirahase, Hiroaki; Hazawa, Masaharu; Wong, Richard W.; Todo, Tomoki; Hirao, Atsushi; Hinoi, Eiichi

doi:10.1038/s41388-021-01745-1

Cited by 43 publications

(34 citation statements)

References 56 publications

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“…Interestingly, we confirmed our hypothesis through TCGA and validated them in CGGA and experiments. At the same time, the mechanisms behind RCN1 were also explored and the identified pathways were consistent with previous studies (Fukasawa et al, 2021;Pucci et al, 2021;Sighel et al, 2021;Xue et al, 2021). The convenient access to the public database allows us for the application of large-scale gene expression profiling and database mining for potential correlation between genes and overall survival of a variety of malignancies including GBM (Aldape et al, 2015;Zhou et al, 2021).…”

Section: Discussionsupporting

confidence: 85%

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Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme

Chen

Liang

et al. 2021

Front. Mol. Biosci.

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Glioblastoma multiform is a lethal primary brain tumor derived from astrocytic, with a poor prognosis in adults. Reticulocalbin-1 (RCN1) is a calcium-binding protein, dysregulation of which contributes to tumorigenesis and progression in various cancers. The present study aimed to identify the impact of RCN1 on the outcomes of patients with Glioblastoma multiforme (GBM). The study applied two public databases to require RNA sequencing data of Glioblastoma multiform samples with clinical data for the construction of a training set and a validation set, respectively. We used bioinformatic analyses to determine that RCN1 could be an independent factor for the overall survival of Glioblastoma multiform patients. In the training set, the study constructed a predictive prognostic model based on the combination of RCN1 with various clinical parameters for overall survival at 0.5-, 1.0-, and 1.5-years, as well as developed a nomogram, which was further validated by validation set. Pathways analyses indicated that RCN1 was involved in KEAS and MYC pathways and apoptosis. In vitro experiments indicated that RCN1 promoted cell invasion of Glioblastoma multiform cells. These results illustrated the prognostic role of RCN1 for overall survival in Glioblastoma multiform patients, indicated the promotion of RCN1 in cell invasion, and suggested the probability of RCN1 as a potential targeted molecule for treatment in Glioblastoma multiform.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 82%

Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme

Chen

Liang

et al. 2021

Front. Mol. Biosci.

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“…For example, a developmentally programmed reduction in CDK8 expression is known to be associated with naive pluripotency during animal development in vivo, and chemical inhibition of CDK8/19 kinase activity has been shown sufficient to revert primed pluripotent stem cells to a naive pluripotent state in vitro (72,73). Furthermore, CDK8, through a mechanism dependent upon cellular MYC (c-MYC), has been shown to promote cancer stem cell selfrenewal and tumorigenicity in colon and brain cancers (74,75). These findings are germane to the pathogenesis of UFs, since the vast majority of these tumors are presumed to arise from genetic transformation of myometrial stem/progenitor cells through somatic mutations in MED12 that disrupt CDK8/19 kinase activity.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of the mediator kinase-dependent myometrial stem cell phosphoproteome

et al. 2021

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Objective: To identify, in myometrial stem/progenitor cells, the presumptive cell of origin for uterine fibroids, substrates of Mediatorassociated cyclin dependent kinase 8/19 (CDK8/19), which is known to be disrupted by uterine fibroid driver mutations in Mediator complex subunit 12 (MED12). Design: Experimental study. Setting: Academic research laboratory. Patient(s): Women undergoing hysterectomy for uterine fibroids. Intervention(s): Stable isotopic labeling of amino acids in cell culture (SILAC) coupled with chemical inhibition of CDK8/19 and downstream quantitative phosphoproteomics and transcriptomic analyses in myometrial stem/progenitor cells. Main Outcome Measure(s): High-confidence Mediator kinase substrates identified by SILAC-based quantitative phosphoproteomics were determined using an empirical Bayes analysis and validated orthogonally by in vitro kinase assay featuring reconstituted Mediator kinase modules comprising wild-type or G44D mutant MED12 corresponding to the most frequent uterine fibroid driver mutation in MED12. Mediator kinase-regulated transcripts identified by RNA sequencing were linked to Mediator kinase substrates by computational analyses. Result(s): A total of 296 unique phosphosites in 166 proteins were significantly decreased (R twofold) upon CDK8/19 inhibition, including 118 phosphosites in 71 nuclear proteins representing high-confidence Mediator kinase substrates linked to RNA polymerase II transcription, RNA processing and transport, chromatin modification, cytoskeletal architecture, and DNA replication and repair. Orthogonal validation confirmed a subset of these proteins, including Cut Like Homeobox 1 (CUX1) and Forkhead Box K1 (FOXK1), to be direct targets of MED12-dependent CDK8 phosphorylation in a manner abrogated by the most common uterine fibroid driver mutation (G44D) in MED12, implicating these substrates in disease pathogenesis. Transcriptome-wide profiling of Mediator kinase-inhibited myometrial stem/progenitor cells revealed alterations in cell cycle and myogenic gene expression programs to which Mediator kinase substrates could be linked directly. Among these, CUX1 is an established transcriptional regulator of the cell cycle whose corresponding gene on chromosome 7q is the locus for a recurrent breakpoint in uterine fibroids, linking MED12 and Mediator kinase with CUX1 for the first time in uterine fibroid pathogenesis. FOXK1, a transcriptional regulator of myogenic stem cell fate, was found to be coordinately enriched along with kinase, but not core, Mediator subunits in myometrial stem/progenitor cells compared with differentiated uterine smooth muscle cells. Conclusion(s): These studies identify a new catalog of pathologically and biologically relevant Mediator kinase substrates implicated in the pathogenesis of MED12 mutation-positive uterine fibroids, and further uncover a biochemical basis to link Mediator kinase

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“…It is generally well-known that SOX2 is a critical tumor stem cell marker and maintains stem cell like phenotype [ 29 ]. All the findings above gave a hint that the high level of CDC42EP3 may be conducive to elevated self-renewal potential and tumorigenicity of glioma stem cells [ 30 ]. However, more detailed exploration about the effects of CDC42EP3 expression on inflammatory responses and stemness of stem cells in glioma cells are still required before coming to a conclusion.…”

Section: Discussionmentioning

confidence: 99%

CDC42EP3 promotes glioma progression via regulation of CCND1

Yang

Xie

et al. 2022

Cell Death Dis

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Gliomas are the most common brain malignancies characterized by high degree of aggressiveness and high mortality. However, the underlying mechanism of glioma progression remains unclear. Here, we probed the role of CDC42EP3 (CDC42 effector protein 3) played in glioma development and its potential downstream mechanism. The expression of CDC42EP3 in tumor and normal brain tissues were examined through immunohistochemistry and we found the likelihood of CDC42EP3 overexpression was positively correlated with pathological grading. Patients with higher expression of CDC42EP3 were more likely to suffer from recurrence as well. Through constructing CDC42EP3-knockdown cell models, we discovered that silencing CDC42EP3 significantly restricted cell proliferation and migration but facilitated cell apoptosis in vitro. Inhibition on tumor growth mediated by CDC42EP3 depletion was further verified in vivo. Regarding downstream target of CDC42EP3, we found that it may positively regulate the expression of CCND1 through c-Myc-mediated transcription. Furthermore, our findings affirmed that effects of CDC42EP3 overexpression on cell proliferation, migration and apoptosis could be confined by depleting CCND1. In a word, this study reported the tumor-promoting role of CDC42EP3 in glioma progression which probably functioned through targeting CCND1.

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

Cited by 43 publications

References 56 publications

Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme

Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme

Identification and characterization of the mediator kinase-dependent myometrial stem cell phosphoproteome

CDC42EP3 promotes glioma progression via regulation of CCND1

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