PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

Abstract

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.

PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration

“…S5), and ChIP-qPCR results showed that PRMT6 inhibits the transcriptional regulation of TRAF6 through H3R2me2a at the TRAF6 promoter. The regulatory mark of PRMT6-mediated asymmetric dimethylation of histones is a well-known mechanism that can either activate or repress gene expression [50], and our previous study demonstrated that PRMT6 can enhance the transcription of CDC20 in GBM cells via H3R2me2a [19]. However, these ndings appear to be contradictory to the results presented here.…”

“…8). Moreover, in our previous studies, it has been con rmed that PRMT6 silencing in GBM cells signi cantly inhibits the growth of transplanted tumors and signi cantly prolongs the survival time of xenograft mice [19]. Therefore, our study demonstrates that PRMT6 could contribute to the proliferation and invasiveness of GBM cells in vivo, which is the main reason why PRMT6 is identi ed as an oncogene in glioma.…”

“…Intracerebral xenograft tumor mouse model and HE staining were used to observe PRMT6-mediated GBM cell invasion in brain tissue, as described previously [19].…”

“…Notably, dysregulation of PRMT6 expression, which has been consistently found in numerous studies, correlates with the aggressiveness of various human cancers such as prostate cancer, lung cancer, and gastric cancer [18]. PRMT6 has been identi ed as an oncogene that promotes cell mitosis and proliferation in GBM [19,20], highlighting its signi cance in GBM and suggesting its potential as a therapeutic target. However, it remains to be determined whether PRMT6 is involved in the invasion process of GBM and the underlying mechanism.…”

TRIP13 regulates progression of gastric cancer through mediating ubiquitination modification of DDX21

“…To detect cell proliferation ability, 1 × 10 3 stable transfected MKN45 and HGC27 cells were cultured in 96 well plates and 6 well plates for 6 and 15 days, respectively. As mentioned previously [35], cell viability was detected by cell counting and MTT assay. After staining with crystal violet, the scanning plate clone formation assay was used, and the absorption rate of 560 was nally measured using absolute ethanol to measure nm for statistical analysis.…”