PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

by Selleckchem | Jul 01 2023

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.

Comments:

The provided text describes a study investigating the role and mechanisms of PRMT6, a type I arginine methyltransferase, in promoting glioblastoma (GBM) proliferation. The study found that PRMT6 is overexpressed in glioma tissues and its elevated expression is negatively correlated with poor prognosis in glioma/GBM patients.

The researchers demonstrated that silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0/G1 phase, while overexpressing PRMT6 had the opposite effect. They further discovered that PRMT6 reduces the protein stability of CDKN1B (a protein involved in cell cycle regulation) by promoting its degradation.

Mechanistic investigations revealed that PRMT6 maintains the transcription of CDC20 (a protein associated with cell cycle progression) by activating a specific histone methylation mark called H3R2me2a. CDC20, in turn, interacts with and destabilizes CDKN1B. Rescue experiments confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation through CDC20.

Additionally, the researchers tested a PRMT6 inhibitor called EPZ020411 and found that it attenuated the proliferative effect of GBM cells, suggesting that targeting PRMT6 could be a potential therapeutic strategy for GBM.

In summary, the study uncovers the essential role of PRMT6 in promoting GBM proliferation. It demonstrates that PRMT6 affects GBM cell cycle progression by regulating the stability of CDKN1B through CDC20 and that PRMT6's activity is mediated through H3R2me2a. The findings suggest that targeting the PRMT6-CDC20-CDKN1B axis could be a promising therapeutic approach for GBM.