PRMT3 drives glioblastoma progression by enhancing HIF1A and glycolytic metabolism

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, but the mechanisms underlying tumor growth and progression remain unclear. The protein arginine methyltransferases (PRMTs) regulate a variety of biological processes, however, their roles in GBM growth and progression are not fully understood. In this study, our functional analysis of gene expression networks revealed that among the PRMT family expression of PRMT3 was most significantly enriched in both GBM and low-grade gliomas. Higher PRMT3 expression predicted poorer overall survival rate in patients with gliomas. Knockdown of PRMT3 markedly reduced the proliferation and migration of GBM cell lines and patient-derived glioblastoma stem cells (GSC) in cell culture, while its over-expression increased the proliferative capacity of GSC cells by promoting cell cycle progression. Consistently, stable PRMT3 knockdown strongly inhibited tumor growth in xenograft mouse models, along with a significant decrease in cell proliferation as well as an increase in apoptosis. We further found that PRMT3 reprogrammed metabolic pathways to promote GSC growth via increasing glycolysis and its critical transcriptional regulator HIF1α. In addition, pharmacological inhibition of PRMT3 with a PRMT3-specific inhibitor SGC707 impaired the growth of GBM cells. Thus, our study demonstrates that PRMT3 promotes GBM progression by enhancing HIF1A-mediated glycolysis and metabolic rewiring, presenting a point of metabolic vulnerability for therapeutic targeting in malignant gliomas.

 

Comments:

The provided text describes a study that investigated the role of protein arginine methyltransferase 3 (PRMT3) in the growth and progression of glioblastoma (GBM), the most common and aggressive primary brain tumor. Here are the key findings of the study:

1. Expression of PRMT3: The study found that among the PRMT family, PRMT3 expression was significantly enriched in both GBM and low-grade gliomas.

2. Prognostic Value: Higher PRMT3 expression was associated with poorer overall survival rates in patients with gliomas, suggesting that PRMT3 may serve as a prognostic marker for these tumors.

3. Effects on Cell Growth and Migration: Knockdown of PRMT3 in GBM cell lines and patient-derived glioblastoma stem cells (GSCs) reduced cell proliferation and migration. Conversely, overexpression of PRMT3 increased the proliferative capacity of GSCs by promoting cell cycle progression.

4. In Vivo Tumor Growth: Stable knockdown of PRMT3 in xenograft mouse models resulted in inhibited tumor growth, accompanied by decreased cell proliferation and increased apoptosis.

5. Metabolic Reprogramming: PRMT3 was found to reprogram metabolic pathways in GSCs, promoting their growth by increasing glycolysis, a process that generates energy from glucose. PRMT3 also influenced the activity of HIF1α, a critical transcriptional regulator involved in glycolysis.

6. Therapeutic Potential: Pharmacological inhibition of PRMT3 using a specific inhibitor (SGC707) impaired the growth of GBM cells, suggesting that targeting PRMT3 could be a potential therapeutic strategy for malignant gliomas.

In summary, this study demonstrates that PRMT3 plays a role in promoting the progression of GBM by enhancing HIF1α-mediated glycolysis and metabolic rewiring. Targeting PRMT3 or its downstream metabolic pathways could be a potential therapeutic approach for treating malignant gliomas.