Antitumor Effects of PRMT5 Inhibition in Sarcomas

Patients with advanced soft-tissue sarcomas (STS) have limited treatment options. Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising anticancer target and has been extensively studied in epithelial tumors. However, its biological role and therapeutic potential in STS remain unexplored.

To assess the value of targeting PRMT5 in STS, we first analyzed the prognostic significance of PRMT5 expression in two independent patient cohorts. We then examined the antitumor effects of PRMT5 inhibition using GSK3326595 (GSK595), a potent and selective PRMT5 inhibitor, through a series of in vitro assays, including MTT, apoptosis, cell cycle, clonogenicity, and proliferation assays. In vivo studies using two animal models were conducted to further evaluate the impact of GSK595 on tumor growth. To uncover the underlying mechanisms, we employed RNA sequencing, metabolic pathway analysis, Western blotting, and glucose uptake/lactate production assays.

Our findings revealed that high PRMT5 expression was significantly associated with poorer metastasis-free survival in patients with STS. GSK595 reduced global symmetric dimethylarginine levels, inhibited cell proliferation and clonogenicity in vitro, and suppressed tumor growth in vivo. Additionally, PRMT5 inhibition disrupted aerobic glycolysis by downregulating key glycolytic enzymes and reducing both glucose uptake and lactate production.

This study highlights the role of PRMT5 in regulating STS metabolism and suggests it as a promising therapeutic target. Further research across diverse sarcoma subtypes is needed to validate and expand upon these findings.