Abstract
Cancer stem-like cells (CSCs) is a cell population in glioma with capacity of self-renewal and is critical in glioma tumorigenesis. Parallels between CSCs and normal stem cells suggest that CSCs give rise to tumors. Oncogenic roles of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) have been reported to play a crucial role in glioma tumorigenesis. Herein, we focus on mechanistic contributions of downstream molecules to maintaining stemness of glioma stem-like cells (GSCs). Transcriptional factor, NF-κB, co-locates with MELK/EZH2 complex. Clinically, we observe that the proportion of MELK/EZH2/NF-κB complex is elevated in high-grade gliomas, which is associated with poor prognosis in patients and correlates negatively with survival. We describe the interaction between these three proteins. Specifically, MELK induces EZH2 phosphorylation, which subsequently binds to and methylates NF-κB, leading to tumor proliferation and persistence of stemness. Furthermore, the interaction between MELK/EZH2 complex and NF-κB preferentially occurs in GSCs compared with non-stem-like tumor cells. Conversely, loss of this signaling dramatically suppresses the self-renewal capability of GSCs. In conclusion, our findings suggest that the GSCs depend on EZH2 phosphorylation to maintain the immature status and promote self-proliferation through NF-κB methylation, and represent a novel therapeutic target in this difficult to treat malignancy.
Highlights
Glioma is the most common primary malignant brain tumor, accounting for almost 40% of primary central nervous system tumors, of which glioblastoma (GBM) is the leading cause of mortality [1, 2]
We examined maternal embryonic leucine-zipper kinase (MELK), enhancer of zeste homolog 2 (EZH2), and NFκB expression by immunohistochemistry and demonstrated that MELK, EZH2, and NF-κB were abundantly enriched in the nuclei of high-grade gliomas with the average score ranking from 1.2 to 1.8, compared with the low-grade and normal adjacent tissues (Figure 1A)
To further confirm the expression profiles, we examined expression of MELK, EZH2, and NF-κB at protein and RNA levels and found that the EZH2 and NF-κB expression was markedly increased in the surgical GBM samples utilizing the immunoblotting and qPCR investigation though there was not detectable difference at MELK protein level (p < 0.01 and p < 0.001, Figure 1C)
Summary
Glioma is the most common primary malignant brain tumor, accounting for almost 40% of primary central nervous system tumors, of which glioblastoma (GBM) is the leading cause of mortality [1, 2]. In spite of significant advances in diagnostic and therapeutic approaches, the median survival of GBM patients remains low and about 14.2 months [3, 4]. This could be attributed to traditional treatment producing limited efficacy on MELK/EZH2/NF-κB Axis in GSCs the subset of tumor cells with the potential to self-renew, termed cancer stem-like cells (CSCs) [5, 6]. The pathways mediating the stemness of normal neural stem cells (NSCs), such as Notch, WNT/β-catenin and Hedgehog signaling, are critical in glioma stem-like cells (GSCs) to drive tumorigenicity. Comprehensive understanding of biological behaviors of GSCs is required for development of targeted therapy, which spares non-malignant NSCs intact
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