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.
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