PRMT6, a type I arginine methyltransferase, di-methylates the arginine residues of both histones and non-histones asymmetrically. Increasing evidence indicates that PRMT6 plays a tumor mediator involved in human malignancies. Here, we aim to uncover the essential role and underlying mechanisms of PRMT6 in promoting glioblastoma (GBM) proliferation. Investigation of PRMT6 expression in glioma tissues demonstrated that PRMT6 is overexpressed, and elevated expression of PRMT6 is negatively correlated with poor prognosis in glioma/GBM patients. Silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0/G1 phase, while overexpressing PRMT6 had opposite results. Further, we found that PRMT6 attenuates the protein stability of CDKN1B by promoting its degradation. Subsequent mechanistic investigations showed that PRMT6 maintains the transcription of CDC20 by activating histone methylation mark (H3R2me2a), and CDC20 interacts with and destabilizes CDKN1B. Rescue experimental results confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation via CDC20. We also verified that the PRMT6 inhibitor (EPZ020411) could attenuate the proliferative effect of GBM cells. Our findings illustrate that PRMT6, an epigenetic mediator, promotes CDC20 transcription via H3R2me2a to mediate the degradation of CDKN1B to facilitate GBM progression. Targeting PRMT6-CDC20-CDKN1B axis might be a promising therapeutic strategy for GBM.

Background SPRY4‐IT1 (SPRY4 intronic transcript 1) is a long non‐coding RNA (lncRNA) that has been identified as a novel oncogene in various cancers, including glioma. However, its function and underlying mechanism in glioma remain largely unclear. Here, we investigated the role of SPRY4‐IT1 in the development of glioma and its underlying mechanism. Methods Bioinformatics analysis and RT‐qPCR assay were used to examine the expression of SPRY4‐IT1 in glioma tissues. The CCK‐8, EdU, and Xenograft tumor assays wereperformed to assess the proliferation effect of glioma cells. The tube forming assay and Chick Embryo Chorioallantoic Membrane (CAM) assay were conducted to detect the angiogenesis effect of HUVECs. RNA‐sequencing, western blotting, RT‐qPCR, ELISA, and IHC assays were employed to verify the regulatory mechanism of the SPRY4‐IT1/ miR‐101‐3p/EZH2/VEGFA axis. Results Analysis of the TCGA dataset and data from our own cohort demonstrated that SPRY4‐IT1 was overexpressed in patients with glioma, and high SPRY4‐IT1 expression correlated with poor prognosis. In vitro and in vivo experiments showed that SPRY4‐IT1 promoted the proliferation of glioma cells. RNA sequencing and Gene Ontology (GO) enrichment analysis indicated significant enrichment of angiogenesis. HUVEC tube forming assay and CAM assay confirmed that SPRY4‐IT1 could induce angiogenesis of glioma cells in vitro and in vivo. Mechanistically, SPRY4‐IT1 upregulated EZH2 expression by sponging miR‐101‐3p to induce VEGFA expression in glioma cells. Moreover, SPRY4‐IT1 activated the VEGFR2/AKT/ERK1/2 pathway in HUVECs mediated by glioma cells. Rescue experiments further confirmed that SPRY4‐IT1 promoted glioma cell proliferation and angiogenesis via the miR‐101‐3p/EZH2/VEGFA signaling axis. Conclusions Our findings provide compelling evidence showing that SPRY4‐IT1 upregulated EZH2 to induce VEGFA by sponging miR‐101‐3p, thereby achieving cell proliferation and angiogenesis in glioma. Therefore, targeting SPRY4‐IT1/miR‐101‐3p/EZH2/VEGFA axis may improve the outcomes of patients with glioma.

Nuclear transcription factor Mesenchyme Homeobox 2 (MEOX2) is a homeobox gene that is originally discovered to suppress the growth of vascular smooth muscle and endothelial cells. However, whether or not it is connected to cancer is yet unknown. Here, we report that MEOX2 functions as a tumor-initiating element in glioma. Bioinformatic analyses of public databases and investigation of MEOX2 expression in patients with glioma demonstrated that MEOX2 was abundant at both mRNA and protein levels in glioma. MEOX2 expression was shown to be inversely linked with the prognosis of glioma patients. MEOX2 inhibition changed the morphology of glioma cells, inhibited cell proliferation and motility, whereas had no effect on cell apoptosis. Besides, silencing MEOX2 also hampered the epithelial-mesenchymal transition (EMT), focal adhesion formation, and F-actin assembly. Overexpression of MEOX2 exhibited opposite effects. Importantly, RNA-sequencing, ChIP-qPCR assay, and luciferase reporter assay revealed Cathepsin S (CTSS) as a novel transcriptional target of MEOX2 in glioma cells. Consistently, MEOX2 causes glioma tumor development in mice and greatly lowers the survival period of tumor-bearing mice. Our findings indicate that MEOX2 promotes tumorigenesis and progression of glioma partially through the regulation of CTSS. Targeting MEOX2-CTSS axis might be a promising alternative for the treatment of glioma.

AimsPrevious studies have indicated that IFI30 plays a protective role in human cancers. However, its potential roles in regulating glioma development are not fully understood.MethodsPublic datasets, immunohistochemistry, and western blotting (WB) were used to evaluate the expression of IFI30 in glioma. The potential functions and mechanisms of IFI30 were examined by public dataset analysis; quantitative real‐time PCR; WB; limiting dilution analysis; xenograft tumor assays; CCK‐8, colony formation, wound healing, and transwell assays; and immunofluorescence microscopy and flow cytometry.ResultsIFI30 was significantly upregulated in glioma tissues and cell lines compared with corresponding controls, and the expression level of IFI30 was positively associated with tumor grade. Functionally, both in vivo and in vitro evidence showed that IFI30 regulated the migration and invasion of glioma cells. Mechanistically, we found that IFI30 dramatically promoted the epithelial–mesenchymal transition (EMT)‐like process by activating the EGFR/AKT/GSK3β/β‐catenin pathway. In addition, IFI30 regulated the chemoresistance of glioma cells to temozolomide directly via the expression of the transcription factor Slug, a key regulator of the EMT‐like process.ConclusionThe present study suggests that IFI30 is a regulator of the EMT‐like phenotype and acts not only as a prognostic marker but also as a potential therapeutic target for temozolomide‐resistant glioma.